ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1969A>C (p.Lys657Gln) (rs727503264)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000811264 SCV000199215 likely pathogenic Hypertrophic cardiomyopathy 2013-11-15 criteria provided, single submitter clinical testing The Lys657Gln variant in MYH7 has now been identified in 1 Caucasian adult with HCM and segregated with disease in 3 affected relatives. It has not been identi fied in large population studies. Lysine (Lys) at position 657 is highly conserv ed in mammals and across evolutionarily distant species and the change to glutam ine (Gln) was predicted to be pathogenic using a computational tool clinically v alidated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clini cal significance.
Invitae RCV000811264 SCV000951522 uncertain significance Hypertrophic cardiomyopathy 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 657 of the MYH7 protein (p.Lys657Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in a family (PMID: 26337809), and has been observed in an individual affected with this condition (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 164351). 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 is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.

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