ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4679G>A (p.Arg1560Gln) (rs730880806)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000778009 SCV000914118 uncertain significance Cardiomyopathy 2018-10-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the LMM domain of the MYH7 protein, a C-terminal tail region that forms the thick filament backbone and interacts with other proteins. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). This variant has also been identified in 4/276692 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000766461 SCV000208601 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing The R1560Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1560Q 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. The R1560Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000628848 SCV000749755 uncertain significance Hypertrophic cardiomyopathy 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1560 of the MYH7 protein (p.Arg1560Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs730880806, ExAC 0.009%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181262). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158666 SCV000280354 uncertain significance not specified 2013-01-07 no assertion criteria provided clinical testing 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.Arg1560Gln (R1560Q; c.4679 G>A) in the MYH7 gene. We classify it as a variant of unknown significance as well. This variant is completely novel and has not previously been reported in individuals with HCM. There is no published segregation data. Variation at one nearby residue has been reported in the HGMD to be associated with HCM: Glu1555Lys. This may support the functional importance of this region of the protein. This is a non-conservative amino acid change, resulting in the replacement of an arginine (basic) with a glutamine (polar). Arginine at this location is 100% conserved across 9 mammalian species. The adjacent residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Possibly Damaging” with a score of 0.562. This variant has not been seen in ~6500 individuals from publicly available population datasets as of January 24, 2014. It is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this codon listed in 1000 Genomes or dbSNP.

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