VCV000042501.25 - ClinVar

NM_000256.3(MYBPC3):c.1037G>A (p.Arg346His)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (9)

9 out of 9 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.1037G>A (p.Arg346His)

Variation ID: 42501 Accession: VCV000042501.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47346260 (GRCh38) [ NCBI UCSC ] 11: 47367811 (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	Jan 7, 2017	Feb 15, 2026	Nov 20, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1037G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg346His	missense
NC_000011.10:g.47346260C>T
NC_000011.9:g.47367811C>T
NG_007667.1:g.11443G>A
LRG_386:g.11443G>A
LRG_386t1:c.1037G>A	LRG_386p1:p.Arg346His

... more HGVS ... less HGVS

Protein change

R346H

Other names

p.R346H:CGC>CAC

Canonical SPDI

NC_000011.10:47346259: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA009714 dbSNP: rs397515883 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 specified	Uncertain significance (1)	criteria provided, single submitter	Aug 10, 2020	RCV000035366.9
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 11, 2024	RCV000766321.6
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 5, 2024	RCV000777949.3
See cases	Uncertain significance (1)	criteria provided, single submitter	Nov 17, 2020	RCV001265536.2
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 20, 2025	RCV001852718.8
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2021	RCV002490473.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Apr 20, 2021	RCV004018739.1

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.
Uncertain significance (Nov 17, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	see cases (Autosomal dominant inheritance)	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations Accession: SCV001443277.2 First in ClinVar: Nov 21, 2020 Last updated: Apr 13, 2025	Comment: show We observed a genetic variants c.1037G>A (p.R346H) in MyBPC3 gene in two unrelated probands diagnosed with left ventricular non-compaction. To our knowledge, this variant is rare. In silico tools (PolyPhen2, MutationTaster, SIFT) classify this variant as deleterious. However, no segregation data was available for both families. In the absence of functional studies we can only classify the c.1037G>A (p.R346H) variant as variant of uncertain clinical significance. (less) Observation: 2 Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Left ventricular noncompaction cardiomyopathy (present) , Cardiac arrhythmia (present) Zygosity: 1 Single Heterozygote Age: 20-29 years Sex: male Comment on evidence: The genetic variant c.1037G>A (p.R346H) was observed in combination with the p.P151L variant in MYH7 gene, also in heterozygous state. Observation 2 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Left ventricular noncompaction cardiomyopathy (present) , Ventricular arrhythmia (present) Zygosity: 1 Single Heterozygote Age: 50-59 years Sex: female

Uncertain significance (Nov 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002177919.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 25132132‚ 27532257‚ 30282064‚ 37652022‚ 38002985 Comment: show This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 346 of the MYBPC3 protein (p.Arg346His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30282064, 37652022, 38002985). ClinVar contains an entry for this variant (Variation ID: 42501). 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. This variant disrupts the p.Arg346 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 25132132; internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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 (Aug 10, 2020) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059014.6 First in ClinVar: May 03, 2013 Last updated: May 29, 2021	Publications: PubMed (1) PubMed: 27532257 Comment: show The p.Arg346His variant in MYBPC3 has been reported in 3 individuals with HCM (Walsh 2017 PMID:27532257, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42501). It was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting. (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: 1

Uncertain significance (Jul 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002785574.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	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 (Apr 20, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004938397.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: show The c.1037G>A (p.R346H) alteration is located in exon 12 (coding exon 12) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1037, causing the arginine (R) at amino acid position 346 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (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 (Dec 21, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208263.14 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: show Also reported in a patient with sudden death and HCM diagnosed on autopsy who also harbors additional cardiogenetic variants including a frameshift variant in the MYBPC3 gene in cis (PMID: 30282064); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Siskind_2022_Preprint, 38002985, 27532257, 30282064) (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 17, 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: SCV005430047.1 First in ClinVar: Dec 14, 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 (4) PubMed: 25611685‚ 27532257‚ 30282064‚ 38002985 Comment: show This missense variant replaces arginine with histidine at codon 346 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 30282064, 38002985). One of these individuals also carried a pathogenic truncation variant in the same gene (PMID: 30282064). In a study of a large cohort of individuals affected with hypertrophic cardiomyopathy, this variant was observed in 3 individuals out of a total of 6179 affected individuals (PMID: 27532257). It has been shown that this variant segregates with disease in two additional affected relatives in two families (PMID: 38002985). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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: 1 Zygosity: 1 Single Heterozygote

Uncertain Significance (Aug 11, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV005879334.1 First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025	Comment: show The MYBPC3 c.1037G>A; p.Arg346His variant (rs397515883, ClinVar Variation ID: 42501) is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (McGurk 2023, Walsh 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.675). Due to limited information, the clinical significance of this variant is uncertain at this time. References: McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. (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 (Jun 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV000914048.2 First in ClinVar: May 20, 2019 Last updated: May 03, 2025	Publications: PubMed (4) PubMed: 25611685‚ 27532257‚ 30282064‚ 38002985 Comment: show This missense variant replaces arginine with histidine at codon 346 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 30282064, 38002985). One of these individuals also carried a pathogenic truncation variant in the same gene (PMID: 30282064). In a study of a large cohort of individuals affected with hypertrophic cardiomyopathy, this variant was observed in 3 individuals out of a total of 6179 affected individuals (PMID: 27532257). It has been shown that this variant segregates with disease in two additional affected relatives in two families (PMID: 38002985). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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

Comment:

We observed a genetic variants c.1037G>A (p.R346H) in MyBPC3 gene in two unrelated probands diagnosed with left ventricular non-compaction. To our knowledge, this variant is rare. In silico tools (PolyPhen2, MutationTaster, SIFT) classify this variant as deleterious. However, no segregation data was available for both families. In the absence of functional studies we can only classify the c.1037G>A (p.R346H) variant as variant of uncertain clinical significance.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 346 of the MYBPC3 protein (p.Arg346His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30282064, 37652022, 38002985). ClinVar contains an entry for this variant (Variation ID: 42501). 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. This variant disrupts the p.Arg346 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 25132132; internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.Arg346His variant in MYBPC3 has been reported in 3 individuals with HCM (Walsh 2017 PMID:27532257, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42501). It was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting.

Comment:

The c.1037G>A (p.R346H) alteration is located in exon 12 (coding exon 12) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1037, causing the arginine (R) at amino acid position 346 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Also reported in a patient with sudden death and HCM diagnosed on autopsy who also harbors additional cardiogenetic variants including a frameshift variant in the MYBPC3 gene in cis (PMID: 30282064); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Siskind_2022_Preprint, 38002985, 27532257, 30282064)

Comment:

This missense variant replaces arginine with histidine at codon 346 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 30282064, 38002985). One of these individuals also carried a pathogenic truncation variant in the same gene (PMID: 30282064). In a study of a large cohort of individuals affected with hypertrophic cardiomyopathy, this variant was observed in 3 individuals out of a total of 6179 affected individuals (PMID: 27532257). It has been shown that this variant segregates with disease in two additional affected relatives in two families (PMID: 38002985). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The MYBPC3 c.1037G>A; p.Arg346His variant (rs397515883, ClinVar Variation ID: 42501) is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (McGurk 2023, Walsh 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.675). Due to limited information, the clinical significance of this variant is uncertain at this time. References: McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hypertrophic Cardiomyopathy in Underrepresented Populations: Clinical and Genetic Landscape Based on a Russian Single-Center Cohort Study.	Chumakova OS	Genes	2023	PMID: 38002985
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
Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series.	Williams N	Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology	2018	PMID: 30282064
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
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
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.	Wang J	European journal of heart failure	2014	PMID: 25132132

Text-mined citations for rs397515883 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 15, 2026