VCV000042752.98 - ClinVar

NM_000256.3(MYBPC3):c.442G>A (p.Gly148Arg)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic (4); Likely pathogenic (10); Uncertain significance (10)

24 out of 28 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.442G>A (p.Gly148Arg)

Variation ID: 42752 Accession: VCV000042752.98

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47350077 (GRCh38) [ NCBI UCSC ] 11: 47371628 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 8, 2015	Jul 27, 2026	Apr 1, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.442G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gly148Arg	missense
NC_000011.10:g.47350077C>T
NC_000011.9:g.47371628C>T
NG_007667.1:g.7626G>A
LRG_386:g.7626G>A
LRG_386t1:c.442G>A	LRG_386p1:p.Gly148Arg

... more HGVS ... less HGVS

Protein change

G148R

Other names

Canonical SPDI

NC_000011.10:47350076:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00006

The Genome Aggregation Database (gnomAD) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00011

Exome Aggregation Consortium (ExAC) 0.00004

Links

ClinGen: CA015105 dbSNP: rs397516050 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYBPC3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4724	4746

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting classifications of pathogenicity (10)	criteria provided, conflicting classifications	Apr 1, 2026	RCV000172015.66
Hypertrophic cardiomyopathy	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Jan 19, 2026	RCV000206268.28
Hypertrophic cardiomyopathy 4	Conflicting classifications of pathogenicity (10)	criteria provided, conflicting classifications	Dec 16, 2025	RCV000578062.19
Primary familial hypertrophic cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Mar 20, 2026	RCV000845519.13
Cardiomyopathy	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	May 6, 2025	RCV001180295.19
Cardiovascular phenotype	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 7, 2025	RCV004018763.4
MYBPC3-related disorder	Likely pathogenic (1)	no assertion criteria provided	Sep 16, 2024	RCV004739324.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 04, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Hypertrophic cardiomyopathy 4	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743584.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Sep 21, 2015) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Hypertrophic cardiomyopathy 4	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744881.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Dec 02, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000927487.1 First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 Comment: Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Hypertrophic cardiomyopathy 4	Illumina Laboratory Services, Illumina Accession: SCV005047007.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain Significance (Sep 11, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004834787.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (16) PubMed: 20378854‚ 20530761‚ 22267749‚ 23861362‚ 25210889‚ 27532257‚ 28679633‚ 29121657‚ 29709087‚ 30763825‚ 31293105‚ 32369506‚ 33495596‚ 33662488‚ 34389451‚ 35288587 Comment: show This missense variant replaces glycine with arginine at codon 148 in the proline-rich domain of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). This variant has been reported in at least 19 unrelated individuals affected with hypertrophic cardiomyopathy from at least ten different families (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587). At least 4 of these affected individuals carried another pathogenic variant in the same gene or a different gene (PMID: 20378854, 20530761, 22267749, 30763825, 35288587; ClinVar SCV000059278.6); in some of these individuals, phenotype was severe or early-onset (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with hypertrophic cardiomyopathy in six heterozygous individuals from three families (PMID: 20378854, 20530761, 35288587). This variant has been observed in individuals lacking a hypertrophic cardiomyopathy phenotype (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European; 0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on the MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals in the literature. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 33 Zygosity: 33 Single Heterozygotes

Pathogenic (Jan 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiovascular phenotype	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987622.2 First in ClinVar: Sep 08, 2019 Last updated: Apr 28, 2025	Comment: show PS4, PVS1_mod, PM2, PP1_mod (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

uncertain significance (Sep 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV006580316.1 First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025	Comment: show Criteria applied: PP3 (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Hypertrophic cardiomyopathy (present) Sex: male

Likely pathogenic (Mar 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413987.2 First in ClinVar: Nov 24, 2024 Last updated: Jan 11, 2026	Publications: PubMed (26) PubMed: 20378854‚ 20474083‚ 20530761‚ 22267749‚ 22958901‚ 23861362‚ 25210889‚ 25335496‚ 25611685‚ 27532257‚ 27650965‚ 28679633‚ 28790153‚ 28794111‚ 29121657‚ 29447731‚ 29709087‚ 29988065‚ 30847666‚ 31293105‚ 32480058‚ 33662488‚ 33782553‚ 35288587‚ 36264615‚ 37652022 Comment: show PP1, PP3, PM3, PS3_supporting, PS4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 2

Uncertain significance (Jun 24, 2013) C Contributing to aggregate classification	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013))	not provided	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000054778.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 Comments (2): Medical sequencing The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)	Observation: 1 Collection method: research Allele origin: unknown Affected status: unknown more Observation 1 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Platform type: next-gen sequencing

Likely pathogenic (Aug 01, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Phosphorus, Inc. Accession: SCV000679776.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (12) PubMed: 18414213‚ 20378854‚ 20474083‚ 20530761‚ 22267749‚ 23861362‚ 24033266‚ 25210889‚ 25335496‚ 25611685‚ 27532257‚ 27650965 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Likely pathogenic (Sep 15, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001473819.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Comment: show The MYBPC3 c.442G>A; p.Gly148Arg variant (rs397516050) is reported in the literature in at least 19 unrelated individuals with cardiomyopathy, some of whom harbored additional uncertain or pathogenic variants in MYBPC3 or other genes associated with cardiomyopathy (Alfares 2010, Burns 2017, Page 2012, van Velzen 2017, van Waning 2018, Viswanathan 2017, Walsh 2017, Zimmerman 2010). This variant also segregated with disease in seven individuals from two families, including four individuals with childhood onset of cardiomyopathy who were also compound heterozygous for a second pathogenic variant in MYBPC3 (Hoedemaekers 2010, Saltzman 2010). This variant is predicted to create a cryptic splice acceptor site (Alamut v.2.11), which is supported by a functional mini-gene assay (Ito 2017); however, the physiological relevance of these observation is unknown. This variant is reported in ClinVar (Variation ID: 42752) and is found in the non-Finnish European population with an allele frequency of 0.015% (13/83,936 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Oct 09, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501906.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (12) PubMed: 20474083‚ 27532257‚ 27650965‚ 28679633‚ 28790153‚ 28794111‚ 29121657‚ 29447731‚ 30291343‚ 30847666‚ 31293105‚ 32480058 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 3 Secondary finding: no Platform type: NGS

Likely pathogenic (May 16, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002042216.3 First in ClinVar: Dec 29, 2021 Last updated: Feb 04, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain Significance (Apr 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059278.7 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (13) PubMed: 20378854‚ 20474083‚ 20530761‚ 22267749‚ 25210889‚ 25335496‚ 27650965‚ 28679633‚ 28790153‚ 28794111‚ 29121657‚ 29447731‚ 29988065 Comment: show proposed classification - variant undergoing re-assessment, contact laboratory (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Oct 08, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV005399740.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (15) PubMed: 20378854‚ 20530761‚ 22267749‚ 27532257‚ 27650965‚ 29709087‚ 29988065‚ 30847666‚ 31293105‚ 32841044‚ 33495597‚ 33662488‚ 33732734‚ 34389451‚ 35288587 Comment: show Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3: 16 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in HCM patients and a single ARVC patient, some of whom harboured other possibly causative variants. It has also been reported as a VUS in an individual with HCM who also harboured a causative de novo variant in FHL1. Familial cases of HCM and/or LVNC were also reported where compound heterozygotes presented with a severe, early onset condition while heterozygotes were either asymptomatic or only mildly affected. Finally, this variant has also been reported in cases of sudden death (ClinVar, VCGS, PMIDs: 27532257, 29988065, 30847666, 29709087, 20530761, 20378854, 22267749, 31293105, 27650965, 33495597, 33732734, 33662488, 34389451, 35288587). (I) 0902 - This variant has moderate evidence for segregation with disease, having segregated within three independent families (personal communication). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jul 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020)	Hypertrophic cardiomyopathy 4	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust Accession: SCV005627610.1 First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025	Publications: PubMed (23) PubMed: 20378854‚ 20474083‚ 20530761‚ 22267749‚ 22958901‚ 23861362‚ 25335496‚ 27532257‚ 27650965‚ 28679633‚ 28790153‚ 28794111‚ 29121657‚ 29709087‚ 29988065‚ 30291343‚ 30847666‚ 31293105‚ 32841044‚ 33662488‚ 33782553‚ 35288587‚ 36264615 Comment: show PP1_Mod PS3_Mod PS4_Mod (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Jun 05, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance)	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV001156274.2 First in ClinVar: Feb 07, 2020 Last updated: Feb 08, 2025	Publications: PubMed (7) PubMed: 20378854‚ 20530761‚ 22267749‚ 22958901‚ 25210889‚ 27532257‚ 27650965 Comment: show This MYBPC3 Gly148Arg variant has previously been identified in association with HCM (Genedx, pers. comm., May 2017; LMM, pers. comm.; Meinke P, et al., 2014; Page SP, et al., 2012; Saltzman AJ, et al., 2010), Anderson Fabry disease (Page SP, et al., 2012) and LVNC (Hoedemaekers YM, et al., 2010). Two studies identified an additional variant known to be pathogenic in the families, although both families demonstrate that Gly148Arg alone may cause HCM (Saltzman AJ, et al., 2010; Hoedemaekers YM, et al., 2010). We have identified the variant in 2 HCM probands. MYBPC3 Gly148Arg has been observed resent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0000665, which is higher than expected for disease-causing HCM variants. The variant is also present in 2 of 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts (Bick AG, et al., 2012). This missense variant is predicted to be benign by in silico tools (SIFT, PolyPhen-HCM, MutationTaster, CADD). In summary the variant has been identified in numerous HCM probands, however due to the relatively high frequency in the general population these finding may be coincidental, furthermore in silico tools predict this variant to be benign, therefore due to the conflicting evidence we classify MYBPC3 Gly148Arg as a variant of "uncertain significance". (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Likely pathogenic (Aug 19, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208215.12 First in ClinVar: Feb 24, 2015 Last updated: Aug 30, 2025	Comment: show In silico analyses support that this missense variant does not alter protein structure/function but has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25210889, 22267749, 18409188, 20474083, 20530761, 30291343, 25335496, 27650965, 20378854, 23861362, 27532257, 28794111, 28679633, 28790153, 29988065, 29447731, 29121657, 29709087, 31293105, 30847666, 32480058, 33662488, 35288587, 36243179, 33782553, 36264615, 37652022, 39633578, 38642550, 30763825) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jul 07, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004938689.3 First in ClinVar: May 01, 2024 Last updated: Oct 05, 2025	Publications: PubMed (11) PubMed: 20378854‚ 20530761‚ 22267749‚ 25210889‚ 28794111‚ 29447731‚ 30763825‚ 33662488‚ 37652022‚ 38642550‚ 39633578 Comment: show The c.442G>A (p.G148R) alteration is located in exon 4 (coding exon 4) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 442, causing the glycine (G) at amino acid position 148 to be replaced by an arginine (R). However, this variant likely exhibits low penetrance in the heterozygous state and may represent a risk factor that manifests clinically only in the presence of additional genetic or environmental factors. Based on data from gnomAD, the A allele has an overall frequency of 0.007% (13/200668) total alleles studied. The highest observed frequency was 0.016% (13/83936) of European (non-Finnish) alleles. This variant has been detected in cohorts or patients with various cardiovascular phenotypes including hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), arrhythmogenic right ventricular cardiomyopathy (ARVC), and dilated cardiomyopathy (DCM), and has been reported in families, frequently co-occurring with additional alterations in MYBPC3 and other cardiac-related genes where compound heterozygous cases have presented with severe or early-onset phenotype (Hoedemaekers, 2010; Saltzman, 2010; Page, 2012; Meinke, 2014; van Velzen, 2017; van Waning, 2018; Te Rijdt, 2019; Alimohamed, 2021). In one or more case control studies, this variant was found to be associated with MYBPC3-related hypertrophic cardiomyopathy (McGurk, 2023; Meisner, 2025). This nucleotide position is well conserved in available vertebrate species. Functional studies in patient-derived induced pluripotent stem cells suggest this variant causes myocyte hypertrophy and sarcomere disorganization; however, the physiological relevance of these findings are unclear (Kinnear, 2024). RNA studies have demonstrated that this alteration results in an incomplete splice defect in the set of samples tested (Ambry internal data; Meisner, 2025). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Jan 19, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259913.14 First in ClinVar: Jan 31, 2016 Last updated: Feb 15, 2026	Publications: PubMed (13) PubMed: 20378854‚ 20530761‚ 22267749‚ 25210889‚ 27532257‚ 28492532‚ 29661763‚ 29709087‚ 30847666‚ 32369506‚ 32480058‚ 32588587‚ 37652022 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 148 of the MYBPC3 protein (p.Gly148Arg). This variant is present in population databases (rs397516050, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and left ventricular noncompaction cardiomyopathy (LVNC) in isolation as well as with a second variant. It may have a lower penetrance in the heterozygous state than would be expected with other disease-causing alleles in this gene, but can present as severe hypertrophic cardiomyopathy in the presence of a second variant (PMID: 20378854, 20530761, 22267749, 25210889, 27532257, 29661763, 29709087, 30847666, 32369506, 32480058, 32588587, 37652022; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42752). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (May 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001345189.5 First in ClinVar: Jun 22, 2020 Last updated: Feb 15, 2026	Publications: PubMed (20) PubMed: 20378854‚ 20530761‚ 22267749‚ 23861362‚ 25210889‚ 27532257‚ 28679633‚ 29121657‚ 29709087‚ 30763825‚ 31293105‚ 32369506‚ 33495596‚ 33662488‚ 34389451‚ 35288587‚ 37652022‚ 38489124‚ 38757491‚ 39633578 Comment: show This missense variant replaces glycine with arginine at codon 148 of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction suggests that this variant may not impact protein structure and function. Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). RNA studies using cardiomyocytes derived from induced pluripotent stem cells have shown that this variant may cause partial alternative splicing and an intermediate size effect on MyBP-C protein (PMID: 39633578). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587, 37652022, 38489124, 38757491). At least 4 of these individuals carried another pathogenic variant (PMID: 20378854, 20530761, 22267749, 30763825, 35288587ClinVar SCV000059278.6)in some of these individuals, phenotype was severe (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with disease in 6 heterozygous individuals from 3 families (PMID: 20378854, 20530761, 35288587). This variant has also been observed in unaffected individuals (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Likely pathogenic (Mar 20, 2026) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Primary familial hypertrophic cardiomyopathy	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803348.2 First in ClinVar: Mar 30, 2024 Last updated: May 03, 2026	Publications: PubMed (13) PubMed: 18409188‚ 20378854‚ 20530761‚ 22267749‚ 27532257‚ 27650965‚ 28679633‚ 28790153‚ 29121657‚ 29447731‚ 29661763‚ 33662488‚ 35288587 Comment: show Variant summary: MYBPC3 c.442G>A (p.Gly148Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 6.5e-05 in 169270 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in MYBPC3, allowing no conclusion about variant significance. c.442G>A has been observed in individuals affected with Hypertrophic Cardiomyopathy or Left Ventricular Noncompaction Cardiomyopathy, including cases where it was found in the compound heterozygous state together with a second pathogenic variant in individuals affected in childhood and the variant has also been found to segregate within affected families (e.g. Fokstuen_ 2008, Hoedemaekers_2010, Saltzman_2010, Page_2012, Sabater-Molina_2013, Christiansen_2016, Burns_2017, van Velzen_2017, Walsh_ 2017, Viswanathan_2018, van Waning_2018, Alimohamed_2021, Lesurf_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33662488, 28790153, 27650965, 18409188, 20530761, 28679633, 35288587, 22267749, 20378854, 29121657, 27532257, 29661763, 29447731). ClinVar contains an entry for this variant (Variation ID: 42752). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely Pathogenic (Dec 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Institute of Immunology and Genetics Kaiserslautern Accession: SCV007596703.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Comment: show ACMG Criteria: PS4, PM2_P, PM3; Variant was found in homozygous state. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Hypertrophic cardiomyopathy (present)

Pathogenic (Apr 01, 2026) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001148286.40 First in ClinVar: Feb 03, 2020 Last updated: Jul 27, 2026	Comment: show MYBPC3: PVS1, PS4, PM2:Supporting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 5

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001954861.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Sep 16, 2024) N Not contributing to aggregate classification	no assertion criteria provided	MYBPC3-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005360314.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show The MYBPC3 c.442G>A variant is predicted to result in the amino acid substitution p.Gly148Arg. This patient is heterozygous in the MYBPC3 gene for a sequence variant designated c.442G>A, which is predicted to result in the amino acid substitution p.Gly148Arg. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy or sudden unexplained death (Page et al. 2012. PubMed ID: 22267749; Meinke et al. 2014. PubMed ID: 25210889; Christiansen. 2016. PubMed ID: 27650965; Burns. 2017. PubMed ID: 28790153; Walsh. 2017. PubMed ID: 27532257). Additionally, this variant has been found to be in trans with a second MYBPC3 variant and segregated with hypertrophic cardiomyopathy in several family members who were heterozygous for only the c.442G>A variant (Hoedemaekers et al. 2010. PubMed ID: 20530761; Saltzman et al. 2010. PubMed ID: 20378854; van Velzen. 2017. PubMed ID: 28794111; van Waning. 2018. PubMed ID: 29447731). In silico tools and RNA sequencing data indicate this variant may impact splicing (Supplemental dataset 6 - Ito. 2017. PubMed ID: 28679633). This variant has conflicting interpretations of pathogenicity of uncertain and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42752/). Based on the available evidence, we consider the MYBPC3 c.442G>A variant to be likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Hypertrophic cardiomyopathy 4	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733076.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001923468.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This missense variant replaces glycine with arginine at codon 148 in the proline-rich domain of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). This variant has been reported in at least 19 unrelated individuals affected with hypertrophic cardiomyopathy from at least ten different families (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587). At least 4 of these affected individuals carried another pathogenic variant in the same gene or a different gene (PMID: 20378854, 20530761, 22267749, 30763825, 35288587; ClinVar SCV000059278.6); in some of these individuals, phenotype was severe or early-onset (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with hypertrophic cardiomyopathy in six heterozygous individuals from three families (PMID: 20378854, 20530761, 35288587). This variant has been observed in individuals lacking a hypertrophic cardiomyopathy phenotype (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European; 0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on the MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals in the literature. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance.

Comment:

The MYBPC3 c.442G>A; p.Gly148Arg variant (rs397516050) is reported in the literature in at least 19 unrelated individuals with cardiomyopathy, some of whom harbored additional uncertain or pathogenic variants in MYBPC3 or other genes associated with cardiomyopathy (Alfares 2010, Burns 2017, Page 2012, van Velzen 2017, van Waning 2018, Viswanathan 2017, Walsh 2017, Zimmerman 2010). This variant also segregated with disease in seven individuals from two families, including four individuals with childhood onset of cardiomyopathy who were also compound heterozygous for a second pathogenic variant in MYBPC3 (Hoedemaekers 2010, Saltzman 2010). This variant is predicted to create a cryptic splice acceptor site (Alamut v.2.11), which is supported by a functional mini-gene assay (Ito 2017); however, the physiological relevance of these observation is unknown. This variant is reported in ClinVar (Variation ID: 42752) and is found in the non-Finnish European population with an allele frequency of 0.015% (13/83,936 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered likely pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3: 16 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in HCM patients and a single ARVC patient, some of whom harboured other possibly causative variants. It has also been reported as a VUS in an individual with HCM who also harboured a causative de novo variant in FHL1. Familial cases of HCM and/or LVNC were also reported where compound heterozygotes presented with a severe, early onset condition while heterozygotes were either asymptomatic or only mildly affected. Finally, this variant has also been reported in cases of sudden death (ClinVar, VCGS, PMIDs: 27532257, 29988065, 30847666, 29709087, 20530761, 20378854, 22267749, 31293105, 27650965, 33495597, 33732734, 33662488, 34389451, 35288587). (I) 0902 - This variant has moderate evidence for segregation with disease, having segregated within three independent families (personal communication). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

This MYBPC3 Gly148Arg variant has previously been identified in association with HCM (Genedx, pers. comm., May 2017; LMM, pers. comm.; Meinke P, et al., 2014; Page SP, et al., 2012; Saltzman AJ, et al., 2010), Anderson Fabry disease (Page SP, et al., 2012) and LVNC (Hoedemaekers YM, et al., 2010). Two studies identified an additional variant known to be pathogenic in the families, although both families demonstrate that Gly148Arg alone may cause HCM (Saltzman AJ, et al., 2010; Hoedemaekers YM, et al., 2010). We have identified the variant in 2 HCM probands. MYBPC3 Gly148Arg has been observed resent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0000665, which is higher than expected for disease-causing HCM variants. The variant is also present in 2 of 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts (Bick AG, et al., 2012). This missense variant is predicted to be benign by in silico tools (SIFT, PolyPhen-HCM, MutationTaster, CADD). In summary the variant has been identified in numerous HCM probands, however due to the relatively high frequency in the general population these finding may be coincidental, furthermore in silico tools predict this variant to be benign, therefore due to the conflicting evidence we classify MYBPC3 Gly148Arg as a variant of "uncertain significance".

Comment:

In silico analyses support that this missense variant does not alter protein structure/function but has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25210889, 22267749, 18409188, 20474083, 20530761, 30291343, 25335496, 27650965, 20378854, 23861362, 27532257, 28794111, 28679633, 28790153, 29988065, 29447731, 29121657, 29709087, 31293105, 30847666, 32480058, 33662488, 35288587, 36243179, 33782553, 36264615, 37652022, 39633578, 38642550, 30763825)

Comment:

The c.442G>A (p.G148R) alteration is located in exon 4 (coding exon 4) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 442, causing the glycine (G) at amino acid position 148 to be replaced by an arginine (R). However, this variant likely exhibits low penetrance in the heterozygous state and may represent a risk factor that manifests clinically only in the presence of additional genetic or environmental factors. Based on data from gnomAD, the A allele has an overall frequency of 0.007% (13/200668) total alleles studied. The highest observed frequency was 0.016% (13/83936) of European (non-Finnish) alleles. This variant has been detected in cohorts or patients with various cardiovascular phenotypes including hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), arrhythmogenic right ventricular cardiomyopathy (ARVC), and dilated cardiomyopathy (DCM), and has been reported in families, frequently co-occurring with additional alterations in MYBPC3 and other cardiac-related genes where compound heterozygous cases have presented with severe or early-onset phenotype (Hoedemaekers, 2010; Saltzman, 2010; Page, 2012; Meinke, 2014; van Velzen, 2017; van Waning, 2018; Te Rijdt, 2019; Alimohamed, 2021). In one or more case control studies, this variant was found to be associated with MYBPC3-related hypertrophic cardiomyopathy (McGurk, 2023; Meisner, 2025). This nucleotide position is well conserved in available vertebrate species. Functional studies in patient-derived induced pluripotent stem cells suggest this variant causes myocyte hypertrophy and sarcomere disorganization; however, the physiological relevance of these findings are unclear (Kinnear, 2024). RNA studies have demonstrated that this alteration results in an incomplete splice defect in the set of samples tested (Ambry internal data; Meisner, 2025). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 148 of the MYBPC3 protein (p.Gly148Arg). This variant is present in population databases (rs397516050, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and left ventricular noncompaction cardiomyopathy (LVNC) in isolation as well as with a second variant. It may have a lower penetrance in the heterozygous state than would be expected with other disease-causing alleles in this gene, but can present as severe hypertrophic cardiomyopathy in the presence of a second variant (PMID: 20378854, 20530761, 22267749, 25210889, 27532257, 29661763, 29709087, 30847666, 32369506, 32480058, 32588587, 37652022; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42752). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

This missense variant replaces glycine with arginine at codon 148 of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction suggests that this variant may not impact protein structure and function. Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). RNA studies using cardiomyocytes derived from induced pluripotent stem cells have shown that this variant may cause partial alternative splicing and an intermediate size effect on MyBP-C protein (PMID: 39633578). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587, 37652022, 38489124, 38757491). At least 4 of these individuals carried another pathogenic variant (PMID: 20378854, 20530761, 22267749, 30763825, 35288587ClinVar SCV000059278.6)in some of these individuals, phenotype was severe (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with disease in 6 heterozygous individuals from 3 families (PMID: 20378854, 20530761, 35288587). This variant has also been observed in unaffected individuals (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance.

Comment:

Variant summary: MYBPC3 c.442G>A (p.Gly148Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 6.5e-05 in 169270 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in MYBPC3, allowing no conclusion about variant significance. c.442G>A has been observed in individuals affected with Hypertrophic Cardiomyopathy or Left Ventricular Noncompaction Cardiomyopathy, including cases where it was found in the compound heterozygous state together with a second pathogenic variant in individuals affected in childhood and the variant has also been found to segregate within affected families (e.g. Fokstuen_ 2008, Hoedemaekers_2010, Saltzman_2010, Page_2012, Sabater-Molina_2013, Christiansen_2016, Burns_2017, van Velzen_2017, Walsh_ 2017, Viswanathan_2018, van Waning_2018, Alimohamed_2021, Lesurf_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33662488, 28790153, 27650965, 18409188, 20530761, 28679633, 35288587, 22267749, 20378854, 29121657, 27532257, 29661763, 29447731). ClinVar contains an entry for this variant (Variation ID: 42752). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

The MYBPC3 c.442G>A variant is predicted to result in the amino acid substitution p.Gly148Arg. This patient is heterozygous in the MYBPC3 gene for a sequence variant designated c.442G>A, which is predicted to result in the amino acid substitution p.Gly148Arg. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy or sudden unexplained death (Page et al. 2012. PubMed ID: 22267749; Meinke et al. 2014. PubMed ID: 25210889; Christiansen. 2016. PubMed ID: 27650965; Burns. 2017. PubMed ID: 28790153; Walsh. 2017. PubMed ID: 27532257). Additionally, this variant has been found to be in trans with a second MYBPC3 variant and segregated with hypertrophic cardiomyopathy in several family members who were heterozygous for only the c.442G>A variant (Hoedemaekers et al. 2010. PubMed ID: 20530761; Saltzman et al. 2010. PubMed ID: 20378854; van Velzen. 2017. PubMed ID: 28794111; van Waning. 2018. PubMed ID: 29447731). In silico tools and RNA sequencing data indicate this variant may impact splicing (Supplemental dataset 6 - Ito. 2017. PubMed ID: 28679633). This variant has conflicting interpretations of pathogenicity of uncertain and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42752/). Based on the available evidence, we consider the MYBPC3 c.442G>A variant to be likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy.	Meisner JK	Circulation	2025	PMID: 39633578
Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy.	Bonaventura J	Journal of the American Heart Association	2024	PMID: 38757491
Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction.	Kinnear C	Cell reports. Medicine	2024	PMID: 38642550
Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance.	Murphy J	Irish journal of medical science	2024	PMID: 38489124
The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings.	McGurk KA	American journal of human genetics	2023	PMID: 37652022
Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population.	Bourfiss M	Circulation. Genomic and precision medicine	2022	PMID: 36264615
Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.	Lesurf R	NPJ genomic medicine	2022	PMID: 35288587
Incidence and predictors of respiratory adverse events in children undergoing procedural sedation with intramuscular ketamine in a paediatric emergency department.	Lee JL	Singapore medical journal	2022	PMID: 32588587
The emergency medical service has a crucial role to unravel the genetics of sudden cardiac arrest in young, out of hospital resuscitated patients: Interim data from the MAP-IT study.	Tiesmeier J	Resuscitation	2021	PMID: 34389451
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.	Thompson AD	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33782553
Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy.	Schuldt M	Frontiers in cardiovascular medicine	2021	PMID: 33732734
Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients.	Alimohamed MZ	International journal of cardiology	2021	PMID: 33662488
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.	Tadros R	Nature genetics	2021	PMID: 33495596
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.	Helms AS	Circulation. Genomic and precision medicine	2020	PMID: 32841044
Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants.	Herkert JC	American heart journal	2020	PMID: 32480058
Sex-specific cardiac remodeling in early and advanced stages of hypertrophic cardiomyopathy.	Nijenkamp LLAM	PloS one	2020	PMID: 32369506
Molecular autopsy and family screening in a young case of sudden cardiac death reveals an unusually severe case of FHL1 related hypertrophic cardiomyopathy.	Gaertner-Rommel A	Molecular genetics & genomic medicine	2019	PMID: 31293105
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy.	Te Rijdt WP	Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology	2019	PMID: 30763825
1 in 38 individuals at risk of a dominant medically actionable disease.	Haer-Wigman L	European journal of human genetics : EJHG	2019	PMID: 30291343
Lack of evidence for a causal role of CALR3 in monogenic cardiomyopathy.	Verhagen JMA	European journal of human genetics : EJHG	2018	PMID: 29988065
Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).	Murray B	Journal of cardiovascular electrophysiology	2018	PMID: 29709087
Outcomes of Contemporary Family Screening in Hypertrophic Cardiomyopathy.	van Velzen HG	Circulation. Genomic and precision medicine	2018	PMID: 29661763
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy.	van Waning JI	Journal of the American College of Cardiology	2018	PMID: 29447731
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.	Viswanathan SK	PloS one	2017	PMID: 29121657
Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation.	van Velzen HG	Circulation. Cardiovascular genetics	2017	PMID: 28794111
Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing.	Burns C	Circulation. Cardiovascular genetics	2017	PMID: 28790153
Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.	Ito K	Proceedings of the National Academy of Sciences of the United States of America	2017	PMID: 28679633
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting.	Christiansen SL	European journal of human genetics : EJHG	2016	PMID: 27650965
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685
Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.	Wessels MW	European journal of human genetics : EJHG	2015	PMID: 25335496
Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.	Meinke P	PLoS genetics	2014	PMID: 25210889
A systematic approach to assessing the clinical significance of genetic variants.	Duzkale H	Clinical genetics	2013	PMID: 24033266
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.	Bick AG	American journal of human genetics	2012	PMID: 22958901
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.	Page SP	Circulation. Cardiovascular genetics	2012	PMID: 22267749
The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy.	Hoedemaekers YM	Circulation. Cardiovascular genetics	2010	PMID: 20530761
A novel custom resequencing array for dilated cardiomyopathy.	Zimmerman RS	Genetics in medicine : official journal of the American College of Medical Genetics	2010	PMID: 20474083
Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy.	Saltzman AJ	Circulation research	2010	PMID: 20378854
ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.	Richards CS	Genetics in medicine : official journal of the American College of Medical Genetics	2008	PMID: 18414213
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.	Fokstuen S	Human mutation	2008	PMID: 18409188
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Text-mined citations for rs397516050 ...

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Record last updated Jul 27, 2026