ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2573G>C (p.Arg858Pro) (rs2856897)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621839 SCV000739960 likely pathogenic Cardiovascular phenotype 2016-06-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000808337 SCV000948443 likely pathogenic Hypertrophic cardiomyopathy 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 858 of the MYH7 protein (p.Arg858Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of hypertrophic cardiomyopathy (HCM) (PMID: 21835320, 23674513, 27247418, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 520277). 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.Arg858 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 15358028, 25086479, 24111713, 24093860, 27247418, 27532257, 20975235), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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