VCV000042975.24 - ClinVar

NM_000257.4(MYH7):c.3803G>A (p.Arg1268His)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(2)

7 out of 7 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.3803G>A (p.Arg1268His)

Variation ID: 42975 Accession: VCV000042975.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23419533 (GRCh38) [ NCBI UCSC ] 14: 23888742 (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	Apr 9, 2018	Feb 15, 2026	Sep 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.3803G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Arg1268His	missense
NC_000014.9:g.23419533C>T
NC_000014.8:g.23888742C>T
NG_007884.1:g.21129G>A
LRG_384:g.21129G>A
LRG_384t1:c.3803G>A

... more HGVS ... less HGVS

Protein change

R1268H

Other names

Canonical SPDI

NC_000014.9:23419532: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) 0.00003

Exome Aggregation Consortium (ExAC) 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Links

ClinGen: CA014102 dbSNP: rs397516194 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 specified	Uncertain significance (1)	criteria provided, single submitter	Sep 19, 2016	RCV000035868.6
Cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 13, 2023	RCV000769450.10
Hypertrophic cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Sep 29, 2025	RCV001418310.9
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jan 24, 2020	RCV002354188.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 18, 2025	RCV005621855.1

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 (Dec 13, 2023) 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: SCV004814392.1 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)	Publications: PubMed (3) PubMed: 30359267‚ 30847666‚ 34302607 Comment: show This missense variant replaces arginine with histidine at codon 1268 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666) and in an individual affected with dilated cardiomyopathy (PMID: 34302607). This variant has also been reported de novo in an individual affected with cardiac defects (PMID: 30359267). This variant has been identified in 21/251484 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: 5 Zygosity: Single Heterozygote

Uncertain significance (Jan 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV006301889.1 First in ClinVar: Aug 03, 2025 Last updated: Aug 03, 2025	Comment: show In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with congenital heart malformations, however evidence in support of pathogenicity for this variant was not provided (PMID: 30359267, 36554045); This variant is associated with the following publications: (PMID: 37937776, 36095024, 30359267, 34542152, 33996946, 36554045) (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

Likely benign (Sep 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001620535.6 First in ClinVar: May 16, 2021 Last updated: Feb 15, 2026	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 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000900843.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019	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 (Sep 19, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059519.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Comment: show proposed classification - variant undergoing re-assessment, contact laboratory (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Likely benign (Jan 24, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002622796.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 27532257‚ 30359267 Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV000914058.5 First in ClinVar: May 20, 2019 Last updated: May 03, 2025	Publications: PubMed (3) PubMed: 30359267‚ 30847666‚ 34302607 Comment: show This missense variant replaces arginine with histidine at codon 1268 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666) and in an individual affected with dilated cardiomyopathy (PMID: 34302607). This variant has also been reported de novo in an individual affected with cardiac defects (PMID: 30359267). This variant has been identified in 21/251484 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 arginine with histidine at codon 1268 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666) and in an individual affected with dilated cardiomyopathy (PMID: 34302607). This variant has also been reported de novo in an individual affected with cardiac defects (PMID: 30359267). This variant has been identified in 21/251484 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; Reported in a patient with congenital heart malformations, however evidence in support of pathogenicity for this variant was not provided (PMID: 30359267, 36554045); This variant is associated with the following publications: (PMID: 37937776, 36095024, 30359267, 34542152, 33996946, 36554045)

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-exome sequencing reveals genetic risks of early-onset sporadic dilated cardiomyopathy in the Chinese Han population.	Xiao L	Science China. Life sciences	2022	PMID: 34302607
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole-exome sequencing (WES).	Leung GKC	BMC medical genomics	2018	PMID: 30359267
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 rs397516194 ...

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