ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2593A>G (p.Lys865Glu) (rs730880749)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158550 SCV000208485 likely pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The K865E variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. K865E is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The K865 residue is conserved across mammal species, and in silico analysis predicts K865E is damaging to the protein structure/function. Mutations in the same residue (K865R) and in nearby residues (A862V, S866P, S866Y, A868P) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Additionally, the K865E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, K865E is a good candidate for a disease-causing mutation. The variant is found in HCM panel(s).
Invitae RCV000802005 SCV000941811 pathogenic Hypertrophic cardiomyopathy 2019-04-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 865 of the MYH7 protein (p.Lys865Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in a family (Invitae) and has been observed in several individuals affected with this condition (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181195). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Lys865 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 16858239), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223827 SCV000280328 uncertain significance not specified 2014-04-29 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. MYH7 p.Lys865Glu Given the lack of case data, (reviewed below) we consider this variant a variant of uncertain significance. This variant is novel. It is located in the S2domain in exon 22 of the MYH7 gene. The variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and are more likely to impact secondary structure. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The lysine at codon 865 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Lys865Arg) and nearby codons (Ala862Val, Ser866Pro, Ser866Tyr, Ala868Pro). The variant at the same codon p.Lys865Arg was reported in one individual with HCM in an Italian cohort of 88 patient with HCM. Sequencing was also performed for MYBPC3 and TNNT2 genes, which was negative for this patient. No additional clinical data or segregation was given (Girolami et al., (2006), J Cardiovasc Med) In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 865 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 1/10/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/10/14).

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