NM_000257.4(MYH7):c.1954A>G (p.Arg652Gly) AND not provided

Clinical significance:Pathogenic (Last evaluated: Nov 18, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000223832.3

Allele description [Variation Report for NM_000257.4(MYH7):c.1954A>G (p.Arg652Gly)]

NM_000257.4(MYH7):c.1954A>G (p.Arg652Gly)

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.1954A>G (p.Arg652Gly)
HGVS:
  • NC_000014.9:g.23427242T>C
  • NG_007884.1:g.13420A>G
  • NM_000257.4:c.1954A>GMANE SELECT
  • NP_000248.2:p.Arg652Gly
  • LRG_384t1:c.1954A>G
  • LRG_384:g.13420A>G
  • NC_000014.8:g.23896451T>C
  • NM_000257.2:c.1954A>G
  • NM_000257.3:c.1954A>G
Protein change:
R652G
Links:
dbSNP: rs727504239
NCBI 1000 Genomes Browser:
rs727504239
Molecular consequence:
  • NM_000257.4:c.1954A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000280308Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Dec 5, 2011)
germlineclinical testing

SCV000490654GeneDxcriteria provided, single submitter
Pathogenic
(Nov 18, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided5not providednot providednot providednot providedclinical testing

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280308.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not 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. MYH7 p.Arg652Gly (c.1954A>G) Given the case data, segregation, and absence in individuals not selected for having HCM, we consider this variant likely disease causing. The variant has been seen in at least 4 (and possibly 7) unrelated cases of HCM (not including this patient's family). There is moderate segregation data. There is no ClinVar entry (as of December 23rd, 2014). Ho et al (2002) reported the variant in 4 affected family members from a kindred with HCM. These presumably overlap with later reports by this group (Ho et al 2013, Valente et al 2013, Ho et al 2014)). I found an online presentation from a UK genetics group (Aberdeen) that seems to report they saw this variant in one patient with HCM. Santos et al (2012) observed the variant in one of 80 Portuguese individuals with HCM who underwent analysis of 28 HCM-associated genes. Coppini et al (2014) included three patients with HCM and this variant from their Italian cohort in a paper comparing thin and thick filament HCM. This presumably overlaps with this group's prior report(s) (Olivotto et al 2008). It is unclear whether the patients were related or unrelated. Coto et al reported the variant in 1 of 60 HCM patients who underwent MYH7 analysis. The variant was reported online in 1 of 61,081 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 23rd, 2014). Specifically, the variant was observed in 1 of 33589 individuals of European decent. The phenotype of that individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided5not providednot providednot provided

From GeneDx, SCV000490654.1

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

Description

The R652G variant in the MYH7 gene has been reported previously in association with HCM (Coto et al., 2012; Ho et al., 2002). In the study by Coto et al., R652G was reported in one individual with HCM and was absent in 150 Caucasian controls (Coto et al., 2012). The R652G variant was also reported in one family in which R652G was present in four family members with a HCM phenotype (Ho et al., 2002). R652G results in a non-conservative amino acid substitution of a hydrophilic Arginine with a hydrophobic Glycine at a residue that is conserved across species. In silico analysis predicts R652G is probably damaging to the protein structure/function. Additionally, pathogenic variants in nearby residues (S642L, L658V, M659T, M659I, T660N) have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014), further supporting the functional importance of this region of the protein. Finally, the R652G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret the R652G variant as pathogenic.

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

Last Updated: Jul 7, 2021

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