Submissions for variant NM_002473.6(MYH9):c.257T>A (p.Met86Lys)

dbSNP: rs774334908

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001819666	SCV002070739	likely pathogenic	not provided	2019-05-31	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MYH9 gene demonstrated a sequence change, c.257T>A, in exon 2 that results in an amino acid change, p.Met86Lys. The p.Met86Lys change affects a highly conserved amino acid residue located in a domain of the MYH9 protein that is known to be functional. The p.Met86Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change is absent from large population databases such as EXAC and gnomAD. The p.Met86Lys amino acid change occurs in a region of the MYH9 gene where other missense sequence changes have been described in patients with MYH9-related disorders (Seri et al., 2000; Saposnik et al., 2014; Kanematsu et al., 2016).This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001819666	SCV004333909	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 86 of the MYH9 protein (p.Met86Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1337180). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH9 protein function. 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.