NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser) AND Hypertrophic cardiomyopathy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 20, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000229519.6

Allele description [Variation Report for NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser)]

NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser)

Gene:
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser)
HGVS:
  • NC_000014.9:g.23427723C>T
  • NG_007884.1:g.12939G>A
  • NM_000257.4:c.1750G>AMANE SELECT
  • NP_000248.2:p.Gly584Ser
  • LRG_384t1:c.1750G>A
  • LRG_384:g.12939G>A
  • NC_000014.8:g.23896932C>T
  • NM_000257.2:c.1750G>A
  • NM_000257.3:c.1750G>A
  • P12883:p.Gly584Ser
  • c.1750G>A
Protein change:
G584S
Links:
UniProtKB: P12883#VAR_029436; dbSNP: rs121913626
NCBI 1000 Genomes Browser:
rs121913626
Molecular consequence:
  • NM_000257.4:c.1750G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hypertrophic cardiomyopathy
Identifiers:
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)
OriginMethodCitations
SCV000059394Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Aug 7, 2017)
germlineclinical testing

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

SCV000284258Invitaecriteria provided, single submitter
Pathogenic
(Oct 20, 2020)
germlineclinical testing

PubMed (11)
[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

Citations

PubMed

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.

Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA.

Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6701-6. doi: 10.1073/pnas.1606950113. Epub 2016 May 31.

PubMed [citation]
PMID:
27247418
PMCID:
PMC4914177

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020
See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000059394.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

The p.Gly584Ser variant in MYH7 has been reported in >5 individuals with HCM (Er dmann 2003, Zou 2013, Kapplinger 2014, Homburger 2016, LMM unpublished), and was absent large population studies. Glycine (Gly) at position 584 is highly conser ved in evolution and the change to Serine (Ser) was predicted to be pathogenic u sing a computational tool clinically validated by our laboratory. This tool's pa thogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, another variant at this position, p.Gly584Arg, has been categorized a s pathogenic, supporting that changes at this position are not tolerated. Of not e, this variant lies in the head region of the protein. Missense variants in thi s region have been reported and statistically indicated to be more likely to cau se disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pa thogenic.

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

From Invitae, SCV000284258.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces glycine with serine at codon 584 of the MYH7 protein (p.Gly584Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (rs121913626, ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID:12974739, 23283745, 24510615, 26187847, 26914223). ClinVar contains an entry for this variant (Variation ID: 42862). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MYH7 gene (PMID: 21310275) all suggest that this missense change is likely to be deleterious, and algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing although these predictions have not been confirmed by published functional studies. Furthermore, a different missense substitution at this codon (p.Gly584Arg) is reported to be deleterious (PMID: 24093860,8282798, 1552912, 8335820). This indicates that the glycine residue is important for MYH7 protein function. In summary, this is a missense variant that is absent from population databases, has been reported in affected individuals, and is predicted to have a deleterious effect on protein function, and is located in a residue required for proper protein function. For these reasons it has been classified as Pathogenic.

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

Last Updated: Nov 27, 2021

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