NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg) AND not provided

Clinical significance:Pathogenic (Last evaluated: May 25, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000158511.3

Allele description [Variation Report for NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg)]

NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg)

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.2146G>A (p.Gly716Arg)
Other names:
p.G716R:GGG>AGG
HGVS:
  • NC_000014.9:g.23425980C>T
  • NG_007884.1:g.14682G>A
  • NM_000257.3:c.2146G>A
  • NP_000248.2:p.Gly716Arg
  • LRG_384t1:c.2146G>A
  • LRG_384:g.14682G>A
  • LRG_384p1:p.Gly716Arg
  • NC_000014.8:g.23895189C>T
  • NM_000257.2:c.2146G>A
  • P12883:p.Gly716Arg
  • c.2146G>A
Protein change:
G716R; GLY716ARG
Links:
UniProtKB: P12883#VAR_004583; OMIM: 160760.0018; dbSNP: rs121913638
NCBI 1000 Genomes Browser:
rs121913638
Molecular consequence:
  • NM_000257.3:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
12

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000208446GeneDxcriteria provided, single submitter
Pathogenic
(May 25, 2017)
germlineclinical testing

Citation Link,

SCV000280310Stanford Center for Inherited Cardiovascular Disease,Stanford Universityno assertion criteria providedPathogenic
(Jan 16, 2012)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided12not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000208446.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The G716R pathogenic variant in the MYH7 gene has been published many times in association withHCM, and it has been observed in multiple unrelated individuals tested for HCM at GeneDx (Anan etal., 1994; Hwang et al., 1998; Woo et al., 2003; Richard et al., 2003; Rai et al., 2009; Choi et al.,2010; Marsiglia et al., 2013). Anan et al. (1994) observed this pathogenic variant in three members ofan Italian family; two of whom developed progressive left ventricular wall thinning and systolicdysfunction. Hwang et al. (1998) reported G716R co-segregated with HCM in a large, four-generationKorean family, in which multiple affected family members died of sudden cardiac death at a young age.In addition, the G716R variant has been identified in four unrelated individuals from two larger cohortstested for HCM, and collectively it was not observed in more than 400 control alleles (Woo et al.,2003; Richard et al., 2003). The G716R variant has also been observed as a de novo variant in yetanother individual with HCM (Rai et al., 2009). Additionally, Marsiglia et al. (2013) identified G716Rin three Brazilian patients with HCM. Fujita et al. (1997) used Dictyostelium discoideum as a model todemonstrate that the G716R variant impairs motor function at the molecular level, as G716R mutantsexhibited weak affinity with actin and generated a low level of force.Furthermore, G716R was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. G716R results in a non-conservative amino acid substitution of a Glycineresidue with an Arginine at a position that is conserved across species.In summary, G716R in the MYH7 gene is interpreted as a pathogenic variant.

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

From Stanford Center for Inherited Cardiovascular Disease,Stanford University, SCV000280310.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided12not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly716Arg in the MYH7 gene. The variant has been seen in at least 10 unrelated cases of HCM, with strong segregation data. The variant was first reported by the Seidman group in three affected first degree relatives (Anan et al 1994). Hwang et al (1998) then reported a Korean family with 5 individuals with HCM who all had the variant (two were fourth degree relatives to each other). The same group later reported longterm follow-up on that family noting that all 15 family members with HCM carried the p.Gly716Arg variant. Ackerman et al (2002) reported a patient with HCM and p.Gly716Arg who had a quite significant family history, though unfortunately no genotyping on family members was reported. This is likely the same case that was later reported in van Driest et al 2004. Richard et al (2003) observed the variant in two unrelated individuals with HCM is their French cohort. Woo et al (2003) reported two individuals with HCM and this variant in their Canadian cohort. Millat et al (2010) reported one HCM patient with p.Gly716Arg in their French cohort, which seems to be distinct from the Richard et al cohort. Rai et al (2009) reported this variant arising de novo in a proband with severe hypertrophy who died suddenly. Parental genotypes and paternity were molecularly confirmed. Parents and a brother were reported as phenotypically normal (though it is unclear if they had cardiac evaluations). Most of the reported families had a particularly high penetrance with severe disease. This variant has also been reported in one individual in our center with HCM and a strong family history of HCM and RCM with multiple family members requiring transplant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glycine at codon 716 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon. Variants at nearby codons have been reported in association with HCM (p.Arg712Leu, p.Arg719Trp, p.Arg719Gln, p.Arg719Pro, p.Arg723Cys, p.Arg723Gly). In total the variant has not been seen in ~6,900 published controls and publicly available population datasets. There is no variation at codon 716 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/6/14). Please note, this does not match the patient's ancestry (Hispanic). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/6/14). The variant was not observed in the following published control samples: more than 100 individuals (Anan et al 1994), 100 (Richard et al 2003), 200 (van Driest et al 2004).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided12not providednot providednot provided

Last Updated: Sep 22, 2018