VCV000042564.27 - ClinVar

NM_000256.3(MYBPC3):c.1778C>T (p.Ser593Phe)

Germline

Classification

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

Uncertain significance
Uncertain significance (7)

7 out of 8 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.1778C>T (p.Ser593Phe)

Variation ID: 42564 Accession: VCV000042564.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47342003 (GRCh38) [ NCBI UCSC ] 11: 47363554 (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	Dec 19, 2017	Feb 23, 2026	Jul 22, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1778C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ser593Phe	missense
NC_000011.10:g.47342003G>A
NC_000011.9:g.47363554G>A
NG_007667.1:g.15700C>T
LRG_386:g.15700C>T
LRG_386t1:c.1778C>T	LRG_386p1:p.Ser593Phe

... more HGVS ... less HGVS

Protein change

S593F

Other names

p.S593F:TCC>TTC

Canonical SPDI

NC_000011.10:47342002:G:A

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) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA011087 dbSNP: rs397515924 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	4727	4749

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	Sep 19, 2019	RCV000035431.10
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 22, 2025	RCV000549676.12
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 6, 2025	RCV000766339.3
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 11, 2025	RCV001177055.6
MYBPC3-related disorder	Uncertain significance (1)	no assertion criteria provided	Dec 11, 2023	RCV004549415.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Nov 23, 2020	RCV004018743.1
Hypertrophic cardiomyopathy 4	Uncertain significance (1)	criteria provided, single submitter	Jan 17, 2025	RCV005862743.1

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 23, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004939651.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: show The c.1778C>T (p.S593F) alteration is located in exon 18 (coding exon 18) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 1778, causing the serine (S) at amino acid position 593 to be replaced by a phenylalanine (F). 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 (Jan 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208046.12 First in ClinVar: Feb 24, 2015 Last updated: Jan 19, 2025	Comment: show Identified in patients with HCM in published literature (PMID: 37652022, 27532257); 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: 27532257, 37652022, 22958901) (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 19, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059079.6 First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020	Comment: show The p.Ser593Phe variant in MYBPC3 has been reported in 1 individual with HCM (LMM data). It has also been identified in 3/182674 chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3. (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 (Dec 01, 2023) 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: SCV004842446.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 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)	Comment: show Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-like domain C4 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/179336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. (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: 4 Zygosity: 4 Single Heterozygotes

Uncertain significance (Jan 17, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV006556043.1 First in ClinVar: Oct 18, 2025 Last updated: Oct 18, 2025	Comment: show The MYBPC3 c.1778C>T (p.Ser593Phe) variant has been reported in at least four individuals with hypertrophic cardiomyopathy (Alfares AA et al., PMID: 25611685; Bick AG et al., PMID: 22958901; Harper AR et al., PMID: 33495597; Ito K et al., PMID: 28679633; Walsh R et al., PMID: 27532257). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by seven submitters (Variation ID: 42564). This variant is seen on 3/182,674 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors suggest that the variant does not impact MYBPC3 function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the MYBPC3 c.1778C>T (p.Ser593Phe) variant is uncertain at this time. (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 (Jul 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001341182.5 First in ClinVar: Jun 22, 2020 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 27532257‚ 37652022 Comment: show This missense variant replaces serine with phenylalanine at codon 593 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 37652022). This variant has been identified in 3/182674 chromosomes 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

Uncertain significance (Jul 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000623533.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 27532257‚ 37652022 Comment: show This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 593 of the MYBPC3 protein (p.Ser593Phe). This variant is present in population databases (rs397515924, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 42564). 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 disruptive. 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 (Dec 11, 2023) N Not contributing to aggregate classification	no assertion criteria provided	MYBPC3-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004717474.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show The MYBPC3 c.1778C>T variant is predicted to result in the amino acid substitution p.Ser593Phe. This variant was reported in an individual with hypertrophic cardiomyopathy (Table S1B, Walsh et al 2017. PubMed ID: 27532257). This variant is reported in 0.0038% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47363554-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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

Comment:

The c.1778C>T (p.S593F) alteration is located in exon 18 (coding exon 18) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 1778, causing the serine (S) at amino acid position 593 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Identified in patients with HCM in published literature (PMID: 37652022, 27532257); 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: 27532257, 37652022, 22958901)

Comment:

The p.Ser593Phe variant in MYBPC3 has been reported in 1 individual with HCM (LMM data). It has also been identified in 3/182674 chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3.

Comment:

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-like domain C4 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/179336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.

Comment:

The MYBPC3 c.1778C>T (p.Ser593Phe) variant has been reported in at least four individuals with hypertrophic cardiomyopathy (Alfares AA et al., PMID: 25611685; Bick AG et al., PMID: 22958901; Harper AR et al., PMID: 33495597; Ito K et al., PMID: 28679633; Walsh R et al., PMID: 27532257). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by seven submitters (Variation ID: 42564). This variant is seen on 3/182,674 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors suggest that the variant does not impact MYBPC3 function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the MYBPC3 c.1778C>T (p.Ser593Phe) variant is uncertain at this time.

Comment:

This missense variant replaces serine with phenylalanine at codon 593 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 37652022). This variant has been identified in 3/182674 chromosomes 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:

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 593 of the MYBPC3 protein (p.Ser593Phe). This variant is present in population databases (rs397515924, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 42564). 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 disruptive. 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 MYBPC3 c.1778C>T variant is predicted to result in the amino acid substitution p.Ser593Phe. This variant was reported in an individual with hypertrophic cardiomyopathy (Table S1B, Walsh et al 2017. PubMed ID: 27532257). This variant is reported in 0.0038% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47363554-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
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

Text-mined citations for rs397515924 ...

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 Mar 01, 2026