VCV000181397.29 - ClinVar

NM_000257.4(MYH7):c.5786C>T (p.Thr1929Met)

Germline

Classification

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

Uncertain significance

8 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_000257.4(MYH7):c.5786C>T (p.Thr1929Met)

Variation ID: 181397 Accession: VCV000181397.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23413763 (GRCh38) [ NCBI UCSC ] 14: 23882972 (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	Feb 27, 2016	Feb 15, 2026	Nov 12, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.5786C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Thr1929Met	missense
NC_000014.9:g.23413763G>A
NC_000014.8:g.23882972G>A
NG_007884.1:g.26899C>T
LRG_384:g.26899C>T
LRG_384t1:c.5786C>T
	P12883:p.Thr1929Met

... more HGVS ... less HGVS

Protein change

T1929M

Other names

Canonical SPDI

NC_000014.9:23413762: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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD) 0.00009

The Genome Aggregation Database (gnomAD) 0.00010

Links

ClinGen: CA016477 UniProtKB: P12883#VAR_042842 dbSNP: rs730880918 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.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	4353	5861

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 (2)	criteria provided, multiple submitters, no conflicts	Feb 7, 2023	RCV000168923.11
Primary familial hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Oct 15, 2015	RCV000208216.3
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Nov 12, 2025	RCV000477627.9
Cardiovascular phenotype	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 9, 2025	RCV000620357.5
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 29, 2024	RCV000777941.9

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 (Oct 15, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Variant Classification)	Primary familial hypertrophic cardiomyopathy	Blueprint Genetics Accession: SCV000264101.3 First in ClinVar: Feb 27, 2016 Last updated: Apr 15, 2023 Comment: Found together with pathogenic MYBPC3:NM_000256.3:c.927-9G>A	Publications: PubMed (1) PubMed: 15358028 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: 1

Uncertain significance (Oct 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000740097.6 First in ClinVar: Apr 14, 2018 Last updated: Jan 13, 2025	Publications: PubMed (7) PubMed: 15358028‚ 19666645‚ 21799269‚ 21839045‚ 24793961‚ 27247418‚ 28798025 Comment: show The p.T1929M variant (also known as c.5786C>T), located in coding exon 37 of the MYH7 gene, results from a C to T substitution at nucleotide position 5786. The threonine at codon 1929 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Kubo T et al. Circ. J., 2011 Jul;75:2654-9). This alteration was reported in a proband and three asymptomatic family members (Michels M et al. Eur. Heart J., 2009 Nov;30:2593-8) and has also been reported in conjunction with a second missense alteration in MYH7 (Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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 (Apr 09, 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: SCV006066034.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Comment: show PS4_mod, PM2 (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 (Jan 19, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002541603.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	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 (Feb 07, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208810.13 First in ClinVar: Feb 24, 2015 Last updated: Feb 18, 2023	Comment: show Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Michels et al., 2009; Kubo et al., 2011; Maron et al., 2012; van Velzen et al., 2016; Pajusalu et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25961035, 21799269, 15358028, 28798025, 28378410, 19666645, 21839045, 27247418, 34426522, 32894683, 27476098, 34542152) (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 (Jul 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004814344.2 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 (11) PubMed: 15358028‚ 19666645‚ 21799269‚ 21839045‚ 28378410‚ 28798025‚ 32894683‚ 33495596‚ 33495597‚ 33500567‚ 38938358 Comment: show This missense variant replaces threonine with methionine at codon 1929 of the MYH7 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 21839045, 28378410, 32894683, 33495596, 33495597, 38938358). One of these individuals also carried a different pathogenic variant in the same gene (PMID: 28378410) and another individual also carried a variant in the FHOD3 gene (PMID: 38938358). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025, 33500567). This variant has been identified in 15/282610 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: 10 Zygosity: Single Heterozygote

Uncertain significance (Jul 18, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV000914039.5 First in ClinVar: May 20, 2019 Last updated: May 03, 2025	Publications: PubMed (11) PubMed: 15358028‚ 19666645‚ 21799269‚ 21839045‚ 28378410‚ 28798025‚ 32894683‚ 33495596‚ 33495597‚ 33500567‚ 38938358 Comment: show This missense variant replaces threonine with methionine at codon 1929 of the MYH7 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 21839045, 28378410, 32894683, 33495596, 33495597, 38938358). One of these individuals also carried a different pathogenic variant in the same gene (PMID: 28378410) and another individual also carried a variant in the FHOD3 gene (PMID: 38938358). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025, 33500567). This variant has been identified in 15/282610 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 (Nov 12, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546252.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 15358028‚ 19666645‚ 21799269‚ 28798025‚ 33500567‚ 38938358 Comment: show This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1929 of the MYH7 protein (p.Thr1929Met). This variant is present in population databases (rs730880918, gnomAD 0.009%). This missense change has been observed in individual(s) with left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 28798025, 33500567, 38938358). ClinVar contains an entry for this variant (Variation ID: 181397). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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

Comment:

The p.T1929M variant (also known as c.5786C>T), located in coding exon 37 of the MYH7 gene, results from a C to T substitution at nucleotide position 5786. The threonine at codon 1929 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Kubo T et al. Circ. J., 2011 Jul;75:2654-9). This alteration was reported in a proband and three asymptomatic family members (Michels M et al. Eur. Heart J., 2009 Nov;30:2593-8) and has also been reported in conjunction with a second missense alteration in MYH7 (Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Michels et al., 2009; Kubo et al., 2011; Maron et al., 2012; van Velzen et al., 2016; Pajusalu et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25961035, 21799269, 15358028, 28798025, 28378410, 19666645, 21839045, 27247418, 34426522, 32894683, 27476098, 34542152)

Comment:

This missense variant replaces threonine with methionine at codon 1929 of the MYH7 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 21839045, 28378410, 32894683, 33495596, 33495597, 38938358). One of these individuals also carried a different pathogenic variant in the same gene (PMID: 28378410) and another individual also carried a variant in the FHOD3 gene (PMID: 38938358). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025, 33500567). This variant has been identified in 15/282610 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1929 of the MYH7 protein (p.Thr1929Met). This variant is present in population databases (rs730880918, gnomAD 0.009%). This missense change has been observed in individual(s) with left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 28798025, 33500567, 38938358). ClinVar contains an entry for this variant (Variation ID: 181397). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Major Cardiac Events in Patients and Relatives With Hereditary Hypertrophic Cardiomyopathy.	Nielsen SK	JACC. Advances	2023	PMID: 38938358
Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.	Mazzarotto F	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33500567
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
Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing.	Mattivi CL	Circulation. Genomic and precision medicine	2020	PMID: 32894683
Large gene panel sequencing in clinical diagnostics-results from 501 consecutive cases.	Pajusalu S	Clinical genetics	2018	PMID: 28378410
Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.	Miszalski-Jamka K	Circulation. Cardiovascular genetics	2017	PMID: 28798025
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.	Homburger JR	Proceedings of the National Academy of Sciences of the United States of America	2016	PMID: 27247418
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors.	Maron BJ	Heart rhythm	2012	PMID: 21839045
Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy.	Kubo T	Circulation journal : official journal of the Japanese Circulation Society	2011	PMID: 21799269
Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers.	Michels M	European heart journal	2009	PMID: 19666645
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.	Van Driest SL	Journal of the American College of Cardiology	2004	PMID: 15358028
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Text-mined citations for rs730880918 ...

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