VCV000042723.22 - ClinVar

NM_000256.3(MYBPC3):c.3580G>A (p.Ala1194Thr)

Germline

Classification

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

Uncertain significance
Uncertain significance (6)

6 out of 6 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.3580G>A (p.Ala1194Thr)

Variation ID: 42723 Accession: VCV000042723.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332613 (GRCh38) [ NCBI UCSC ] 11: 47354164 (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 31, 2015	Feb 15, 2026	Nov 24, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3580G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ala1194Thr	missense
NC_000011.10:g.47332613C>T
NC_000011.9:g.47354164C>T
NG_007667.1:g.25090G>A
LRG_386:g.25090G>A
LRG_386t1:c.3580G>A	LRG_386p1:p.Ala1194Thr
	Q14896:p.Ala1194Thr

... more HGVS ... less HGVS

Protein change

A1194T

Other names

Canonical SPDI

NC_000011.10:47332612: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) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00007

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA014361 UniProtKB: Q14896#VAR_019900 dbSNP: rs397516026 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 provided	Uncertain significance (1)	criteria provided, single submitter	Sep 11, 2025	RCV000766735.2
Hypertrophic cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 24, 2025	RCV000793831.12
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Mar 7, 2024	RCV001185757.5
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Oct 29, 2021	RCV002490482.1

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 (Sep 12, 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: SCV004836582.2 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 (4) PubMed: 12707239‚ 18258667‚ 22361390‚ 27532257 Comment: show This missense variant replaces alanine with threonine at codon 1194 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18258667, 27532257) and an infant affected with sudden death (PMID: 22361390). This variant has been identified in 9/280378 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 Number of individuals with the variant: 11 Zygosity: 11 Single Heterozygotes

Uncertain significance (Sep 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000568215.4 First in ClinVar: Jan 31, 2015 Last updated: Oct 05, 2025	Comment: show In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with HCM or suspected HCM in published literature (PMID: 27532257, 12707239); This variant is associated with the following publications: (PMID: 22361390, 21415409, 27532257, 28679633, 12707239, 37652022) (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 (Nov 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000933207.8 First in ClinVar: Aug 14, 2019 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 12707239‚ 22361390‚ 27532257‚ 37652022 Comment: show This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1194 of the MYBPC3 protein (p.Ala1194Thr). This variant is present in population databases (rs397516026, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 22361390, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 42723). 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 (Oct 29, 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: SCV002797001.1 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 04, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059249.5 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (1) PubMed: 12707239 Comment: show Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with HCM (Richard 2003) and one individual with SIDS (Brion 2012). Classified as VUS in Walsh 2017. Clinvar: VUS (GeneDx). Gnomad: 0.02% (5 alleles). Prediction tools are conflicting. (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 (Mar 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001352034.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (4) PubMed: 12707239‚ 18258667‚ 22361390‚ 27532257 Comment: show This missense variant replaces alanine with threonine at codon 1194 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18258667, 27532257) and one infant affected with sudden death (PMID: 22361390). This variant has been identified in 9/280378 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

Comment:

This missense variant replaces alanine with threonine at codon 1194 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18258667, 27532257) and an infant affected with sudden death (PMID: 22361390). This variant has been identified in 9/280378 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:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with HCM or suspected HCM in published literature (PMID: 27532257, 12707239); This variant is associated with the following publications: (PMID: 22361390, 21415409, 27532257, 28679633, 12707239, 37652022)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1194 of the MYBPC3 protein (p.Ala1194Thr). This variant is present in population databases (rs397516026, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 22361390, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 42723). 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:

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with HCM (Richard 2003) and one individual with SIDS (Brion 2012). Classified as VUS in Walsh 2017. Clinvar: VUS (GeneDx). Gnomad: 0.02% (5 alleles). Prediction tools are conflicting.

Comment:

This missense variant replaces alanine with threonine at codon 1194 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18258667, 27532257) and one infant affected with sudden death (PMID: 22361390). This variant has been identified in 9/280378 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.

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
Sarcomeric gene mutations in sudden infant death syndrome (SIDS).	Brion M	Forensic science international	2012	PMID: 22361390
Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy.	Waldmüller S	Clinical chemistry	2008	PMID: 18258667
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.	Richard P	Circulation	2003	PMID: 12707239

Text-mined citations for rs397516026 ...

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