VCV000043064.27 - ClinVar

NM_000257.4(MYH7):c.5342G>A (p.Arg1781His)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Uncertain significance

for Hypertrophic cardiomyopathy

Classification is based on the expert panel submission

Aug 2021 by ClinGen Cardiomyopathy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.5342G>A (p.Arg1781His)

Variation ID: 43064 Accession: VCV000043064.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23415212 (GRCh38) [ NCBI UCSC ] 14: 23884421 (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	Jul 1, 2016	May 3, 2025	Aug 25, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.5342G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Arg1781His	missense
NC_000014.9:g.23415212C>T
NC_000014.8:g.23884421C>T
NG_007884.1:g.25450G>A
LRG_384:g.25450G>A
LRG_384t1:c.5342G>A

... more HGVS ... less HGVS

Protein change

R1781H

Other names

NM_000257.4(MYH7):c.5342G>A

Canonical SPDI

NC_000014.9:23415211: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 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA015985 dbSNP: rs397516246 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	4096	5528

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.
Hypertrophic cardiomyopathy	Uncertain significance (3)	reviewed by expert panel	Aug 25, 2021	RCV000234735.11
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 7, 2023	RCV001550459.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Apr 9, 2024	RCV002345280.4
Congenital myopathy with fiber type disproportion Dilated cardiomyopathy 1S Hypertrophic cardiomyopathy 1 MYH7-related skeletal myopathy Myopathy, myosin storage, autosomal recessive Myosin storage myopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 4, 2021	RCV002477078.1
Cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Mar 4, 2024	RCV005402816.1

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 (Aug 25, 2021) C Contributing to aggregate classification	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	ClinGen Cardiomyopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV001976480.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7f87264e-0238-497f-84ef-902ccd67f99c Comment: show The c.5342G>A (p.Arg1781His) variant in MYH7 has been identified in at least 12 individuals with HCM (PS4_Moderate; Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). This variant was identified in 0.00116% (FAF 95% CI; 2/30616) of South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Uncertain significance (Sep 04, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MYH7-related skeletal myopathy Myosin storage myopathy Hypertrophic cardiomyopathy 1 Myopathy, myosin storage, autosomal recessive Congenital myopathy 4A, autosomal dominant Myosin storage myopathy Dilated cardiomyopathy 1S	Fulgent Genetics, Fulgent Genetics Accession: SCV002792575.1 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 (Aug 07, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059611.7 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 17125710‚ 24111713‚ 27532257‚ 25351510 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

Pathogenic (Dec 04, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284285.8 First in ClinVar: Jul 01, 2016 Last updated: Feb 16, 2025	Publications: PubMed (2) PubMed: 17125710‚ 27532257 Comment: show This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1781 of the MYH7 protein (p.Arg1781His). This variant is present in population databases (rs397516246, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17125710, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 43064). 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 expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as 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 (Jan 21, 2014) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492983.1 First in ClinVar: Jul 01, 2016 Last updated: Jul 01, 2016	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Uncertain significance (Jan 19, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV001770786.3 First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023	Comment: show Variant reported in multiple unrelated individuals with HCM in the published literature or referred for genetic testing at GeneDx; however, few clinical details were provided and some individuals harbor additional cardiogenetic variants (Laredo et al., 2006; Kaski et al., 2009; Lopes et al., 2015; Homburger et al., 2016; Alamo et al., 2017; Mademont-Soler et al., 2017; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 43064; ClinVar); This variant is associated with the following publications: (PMID: 27532257, 17125710, 20031618, 25351510, 28606303, 28771489, 27247418, 29687901, 24111713, 32531501) (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 (Apr 09, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002647064.4 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Publications: PubMed (12) PubMed: 17125710‚ 23396983‚ 27532257‚ 28606303‚ 28771489‚ 28840316‚ 29687901‚ 29875424‚ 32531501‚ 34495297‚ 34542152‚ 35276540 Comment: show The p.R1781H variant (also known as c.5342G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5342. The arginine at codon 1781 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts; however, in some instances clinical detail was limited and co-occurring variants were present, and some reports may overlap (Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; Azevedo O et al. Am. Heart J., 2020 Apr;226:114-126). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Likely pathogenic (Mar 04, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV006064066.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Publications: PubMed (9) PubMed: 17125710‚ 23396983‚ 25351510‚ 27532257‚ 28771489‚ 29875424‚ 32531501‚ 33495597‚ 35276540 Comment: show This missense variant replaces arginine with histidine at codon 1781 in the LMM domain of the MYH7 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 more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 23396983, 25351510, 27532257, 28771489, 29875424, 32531501, 33495597; communication with an external laboratory; ClinVar SCV000284285.6). It has also been reported in one individual affected with sudden cardiac death (PMID: 35276540). This variant has been identified in 5/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (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:

The c.5342G>A (p.Arg1781His) variant in MYH7 has been identified in at least 12 individuals with HCM (PS4_Moderate; Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). This variant was identified in 0.00116% (FAF 95% CI; 2/30616) of South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1781 of the MYH7 protein (p.Arg1781His). This variant is present in population databases (rs397516246, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17125710, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 43064). 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 expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant reported in multiple unrelated individuals with HCM in the published literature or referred for genetic testing at GeneDx; however, few clinical details were provided and some individuals harbor additional cardiogenetic variants (Laredo et al., 2006; Kaski et al., 2009; Lopes et al., 2015; Homburger et al., 2016; Alamo et al., 2017; Mademont-Soler et al., 2017; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 43064; ClinVar); This variant is associated with the following publications: (PMID: 27532257, 17125710, 20031618, 25351510, 28606303, 28771489, 27247418, 29687901, 24111713, 32531501)

Comment:

The p.R1781H variant (also known as c.5342G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5342. The arginine at codon 1781 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts; however, in some instances clinical detail was limited and co-occurring variants were present, and some reports may overlap (Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; Azevedo O et al. Am. Heart J., 2020 Apr;226:114-126). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces arginine with histidine at codon 1781 in the LMM domain of the MYH7 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 more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 23396983, 25351510, 27532257, 28771489, 29875424, 32531501, 33495597; communication with an external laboratory; ClinVar SCV000284285.6). It has also been reported in one individual affected with sudden cardiac death (PMID: 35276540). This variant has been identified in 5/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Benefits and outcomes of a new multidisciplinary approach for the management and financing of sudden unexplained death cases in a forensic setting in Switzerland.	Neubauer J	Forensic science international	2022	PMID: 35276540
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.	Park J	Human molecular genetics	2022	PMID: 34542152
Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.	Yoneda ZT	JAMA cardiology	2021	PMID: 34495297
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy?	Azevedo O	American heart journal	2020	PMID: 32531501
Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center.	Mazzarotto F	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29875424
Thick Filament Protein Network, Functions, and Disease Association.	Wang L	Comprehensive Physiology	2018	PMID: 29687901
Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals.	Sedaghat-Hamedani F	Clinical research in cardiology : official journal of the German Cardiac Society	2018	PMID: 28840316
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.	Mademont-Soler I	PloS one	2017	PMID: 28771489
Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes.	Alamo L	eLife	2017	PMID: 28606303
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
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Genetics of hypertrophic cardiomyopathy in Norway.	Berge KE	Clinical genetics	2014	PMID: 24111713
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
[Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy].	Laredo R	Revista espanola de cardiologia	2006	PMID: 17125710
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7f87264e-0238-497f-84ef-902ccd67f99c	-	-	-	-
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Text-mined citations for rs397516246 ...

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 Jan 03, 2026

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.5342G>A (p.Arg1781His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs397516246 ...