NM_000257.4(MYH7):c.596C>T (p.Ala199Val) AND Hypertrophic cardiomyopathy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Dec 18, 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.596C>T (p.Ala199Val)]

NM_000257.4(MYH7):c.596C>T (p.Ala199Val)

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.596C>T (p.Ala199Val)
Other names:
  • NC_000014.9:g.23431804G>A
  • NG_007884.1:g.8858C>T
  • NM_000257.4:c.596C>TMANE SELECT
  • NP_000248.2:p.Ala199Val
  • LRG_384t1:c.596C>T
  • LRG_384:g.8858C>T
  • NC_000014.8:g.23901013G>A
  • NM_000257.2:c.596C>T
  • NM_000257.3:c.596C>T
Protein change:
dbSNP: rs727504283
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000257.4:c.596C>T - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000203951Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Dec 18, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000835700Invitaecriteria provided, single submitter
(Jun 14, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown53not providednot providednot providedclinical testing



Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA.

Circ Cardiovasc Genet. 2012 Dec;5(6):602-10. doi: 10.1161/CIRCGENETICS.112.963421. Epub 2012 Oct 16.

PubMed [citation]

Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL.

Genet Med. 2015 Nov;17(11):880-8. doi: 10.1038/gim.2014.205. Epub 2015 Jan 22. Erratum in: Genet Med. 2015 Apr;17(4):319.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000203951.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (4)


The p.Ala199Val variant in MYH7 has been identified by our laboratory in at least 3 individuals with HCM and segregated with disease in several affected relatives (including 3 obligate carriers) from 1 family (Pan 2012, Alfares PMID: 25611685, Walsh 2017 PMID: 27532257, LMM unpublished data and personal communication). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177693) was absent from large population studies. Computational prediction tools and conservation analyses are consistent with pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID 27532257). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PP1_Strong, PP3, PM1.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided5not provided3not provided

From Invitae, SCV000835700.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


This sequence change replaces alanine with valine at codon 199 of the MYH7 protein (p.Ala199Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID:  27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 177692). 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). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Nov 27, 2021

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