NM_000257.3(MYH7):c.746G>A (p.Arg249Gln) AND Primary familial hypertrophic cardiomyopathy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1) (Last evaluated: Mar 4, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000036000.3

Allele description [Variation Report for NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)]

NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)

Gene:
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)
Other names:
p.R249Q:CGA>CAA
HGVS:
  • NC_000014.9:g.23431468C>T
  • NG_007884.1:g.9194G>A
  • NM_000257.3:c.746G>A
  • NP_000248.2:p.Arg249Gln
  • LRG_384t1:c.746G>A
  • LRG_384:g.9194G>A
  • LRG_384p1:p.Arg249Gln
  • NC_000014.8:g.23900677C>T
  • NM_000257.2:c.746G>A
  • P12883:p.Arg249Gln
  • c.746G>A
Protein change:
R249Q; ARG249GLN
Links:
UniProtKB: P12883#VAR_004569; OMIM: 160760.0002; dbSNP: 3218713
NCBI 1000 Genomes Browser:
rs3218713
Molecular consequence:
  • NM_000257.3:c.746G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Name:
Primary familial hypertrophic cardiomyopathy (HCM)
Synonyms:
Hypertrophic cardiomyopathy
Identifiers:
MedGen: C0949658; OMIM: PS192600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000059652Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Mar 4, 2016)
germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV000219861CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontariocriteria provided, single submitter
Likely pathogenic
(Sep 24, 2013)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided63not providednot providednot providedclinical testing

Citations

PubMed

Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure.

Arbustini E, Fasani R, Morbini P, Diegoli M, Grasso M, Dal Bello B, Marangoni E, Banfi P, Banchieri N, Bellini O, Comi G, Narula J, Campana C, Gavazzi A, Danesino C, ViganĂ² M.

Heart. 1998 Dec;80(6):548-58. Erratum in: Heart 1999 Mar;81(3):330.

PubMed [citation]
PMID:
10065021
PMCID:
PMC1728869

Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children.

Greber-Platzer S, Marx M, Fleischmann C, Suppan C, Dobner M, Wimmer M.

J Mol Cell Cardiol. 2001 Jan;33(1):141-8.

PubMed [citation]
PMID:
11133230
See all PubMed Citations (14)

Details of each submission

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000059652.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testing PubMed (13)

Description

The p.Arg249Gln variant in MYH7 has been reported in >10 individuals with HCM, including 2 de novo occurrences, and segregated with disease in >30 affected relatives from 3 families (Rosenzweig 1991, Watkins 1992, Posen 1995, Arbustini 1998, Greber-Platzer 2001, Richard 2003, Woo 2003, Kassem 2013). It was absent from large population studies. Arginine (Arg) at position 249 is highly conserved in mammals and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, de novo occurrences, and absence from controls.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided6not provided3not provided

From CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario, SCV000219861.2

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

Description

Mutation positive member of a proband reported by Familion. From Familion report: " This mutation is a class I variant, meaning it is strongly expected to predispose to a cardiomyopathy, such as Hypertrophic cardiomyopathy. In the published literature, MYH7 Arg249Gln has been reported in at least 9 suspected HCM unrelated probands, has been shown to segregate with disease in family studies, and has been functionally characterized as abnormal (Rosenzweig et al. NEJM 1991 325: 1753-1760; Watkins et al. NEJM 1992 326: 1108-1112; Posen et al. Br Heart J 1995 74: 40-46; Sata et al. J Clin Invest. 1996:2866-2873 and others). MYH7 Arg249Gln has not been observed in a PGxHealth control population of over 400 unrelated, ethnically diverse, presumed healthy individuals."

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

Last Updated: Sep 27, 2017