Submissions for variant NM_000257.4(MYH7):c.2478T>A (p.Asn826Lys)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158844	SCV000208779	likely pathogenic	not provided	2011-08-05	criteria provided, single submitter	clinical testing	This mutation is denoted p.Asn826Lys (N826K) at the protein level and c.2478 T>A at the cDNA level. The Asn826Lys variant has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. The Asn826Lys results in a non-conservative amino acid substitution of a neutral Asparagine residue with a positively charged Lysine residue at a position that is class conserved in evolution. In silico analysis predicts Asn826Lys to be damaging to the protein structure/function. Additionally, mutations in nearby codons (Gly823Glu, Val824Ile, Trp827Cys) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of Asn826Lys, although evidence suggests it is likely disease-causing. The variant is found in HCM panel(s).
Invitae	RCV003586159	SCV004337910	uncertain significance	Hypertrophic cardiomyopathy	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 826 of the MYH7 protein (p.Asn826Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181373). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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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