NM_000257.4(MYH7):c.728G>A (p.Arg243His) AND Hypertrophic cardiomyopathy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 26, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000257.4(MYH7):c.728G>A (p.Arg243His)]

NM_000257.4(MYH7):c.728G>A (p.Arg243His)

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.728G>A (p.Arg243His)
Other names:
p.R243H:CGC>CAC; NM_000257.4(MYH7):c.728G>A
  • NC_000014.9:g.23431589C>T
  • NG_007884.1:g.9073G>A
  • NM_000257.4:c.728G>AMANE SELECT
  • NP_000248.2:p.Arg243His
  • LRG_384t1:c.728G>A
  • LRG_384:g.9073G>A
  • LRG_384p1:p.Arg243His
  • NC_000014.8:g.23900798C>T
  • NM_000257.2:c.728G>A
  • NM_000257.3:c.728G>A
  • P12883:p.Arg243His
Protein change:
R243H; ARG243HIS
UniProtKB: P12883#VAR_073876; OMIM: 160760.0040; dbSNP: rs267606910
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000257.4:c.728G>A - missense variant - [Sequence Ontology: SO:0001583]


Hypertrophic cardiomyopathy
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; OMIM: PS192600; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000546234Invitaecriteria provided, single submitter
(Oct 26, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000967720Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Apr 20, 2018)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death.

Chang B, Nishizawa T, Furutani M, Fujiki A, Tani M, Kawaguchi M, Ibuki K, Hirono K, Taneichi H, Uese K, Onuma Y, Bowles NE, Ichida F, Inoue H, Matsuoka R, Miyawaki T; Noncompaction study collaborators..

Mol Genet Metab. 2011 Feb;102(2):200-6. doi: 10.1016/j.ymgme.2010.09.009. Epub 2010 Sep 29.

PubMed [citation]

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000546234.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)


This sequence change replaces arginine with histidine at codon 243 of the MYH7 protein (p.Arg243His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs267606910, ExAC 0.001%). This variant has been reported in several individuals with left ventricular non-compaction cardiomyopathy (LVNC) and to segregate with the disease (PMID: 18506004, 20965760, 21551322). ClinVar contains an entry for this variant (Variation ID: 14126). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). In summary, this is a rare missense variant which has been reported in affected individuals and is predicted to cause a deleterious effect on MYH7 protein function. For these reasons it has been classified as Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000967720.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)


The p.Arg243His variant in MYH7 has been reported in 1 individual with hypertrop hic cardiomyopathy (Arad 2005), 1 with Ebstein anomaly (Sicko 2016), and 1 with left ventricular non-compaction, where it segregated in two affected relatives ( Klaassen 2008). It has been identified in 1/111714 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs2 67606910) and has been reported in ClinVar (Variation ID: 14126). In addition, another amino acid substitution involving this codon, p.Arg243Cys, has also been identified in individuals with HCM (Kubo 2011, Homburger 2016, Viswanathan 2017 ). Computational prediction tools and conservation analysis suggest that the p.A rg243His variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. This variant lies in the head region of th e protein and missense variants in this region have been reported and statistica lly indicated to be more likely to cause disease (Walsh 2016). In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Arg243His variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PM5; PP3.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Sep 29, 2021

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