ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys) (rs730880792)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766457 SCV000208573 uncertain significance not provided 2014-07-03 criteria provided, single submitter clinical testing p.Glu1387Lys (GAG>AAG): c.4159 G>A in exon 30 of the MYH7 gene (NM_000257.2). A missense variant that is likely pathogenic was identified in the MYH7 gene. The E1387K variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The E1387K 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 E1387K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R1382Q, R1382W, A1379T, T1377M) have been reported in association with HCM, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HCM panel(s).
Invitae RCV000457747 SCV000546215 uncertain significance Hypertrophic cardiomyopathy 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1387 of the MYH7 protein (p.Glu1387Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418) and in an individual either affected with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181244). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.
Ambry Genetics RCV000621684 SCV000736922 uncertain significance Cardiovascular phenotype 2017-09-22 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001109893 SCV001267274 uncertain significance Dilated cardiomyopathy 1S 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001109894 SCV001267275 uncertain significance Myosin storage myopathy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001109895 SCV001267276 uncertain significance Myopathy, distal, 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001109896 SCV001267277 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001109896 SCV001433094 uncertain significance Familial hypertrophic cardiomyopathy 1 2019-05-03 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158638 SCV000280347 uncertain significance not specified 2014-07-07 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.Glu1387Lys (c.4159 G>A) in the MYH7 gene. The variant has been seen in at least one unrelated cases of HCM (not including this patient's family). No segregation data is available. GeneDx notes the variant is novel, however I found a report of the variant in a poster from the 2010 European Society of Cardiology meeting (Waldmuller et al 2010, Http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=P2062). I could not find a report of this variant in any publications by the same group. In the poster they report observing the variant in one of 20 patents with "suspected familial HCM" who underwent sequencing of 17 cardiomyopathy associated genes. Ancestry is not noted, however the report is by a German group. No segregation data was reported. The same group also reported on the variant, very likely from the same case, at the 2010 Congress of the German Human Genetics Society (Waldmuller et al 2010). It is not in ClinVar. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The glutamic acid at codon 1387 is completely conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with cardiomyopathy at nearby codons (p.Ala1379Thr (per the Seidman's database), p.Arg1382Gln, p.Arg1382Trp (per GeneDx report, referencing HGMD)). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 1387 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 23rd 2014).There is also no variation at this codon listed in dbSNP (as of July 24th, 2014).

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