Submissions for variant NM_017534.6(MYH2):c.1792G>A (p.Glu598Lys)

dbSNP: rs1555571267

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596856	SCV000705064	uncertain significance	not provided	2017-01-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690809	SCV000818537	uncertain significance	Myopathy, proximal, and ophthalmoplegia	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 598 of the MYH2 protein (p.Glu598Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant myopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499533). 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 not expected to disrupt MYH2 protein function with a negative predictive value of 80%. 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.
Revvity Omics, Revvity	RCV000690809	SCV003809458	uncertain significance	Myopathy, proximal, and ophthalmoplegia	2019-08-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000690809	SCV005690614	uncertain significance	Myopathy, proximal, and ophthalmoplegia	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.1792G>A (p.Glu598Lys) variant in MYH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu598Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submission). Multiple lines of computational evidence (Polyphen - Benign, SIFT - Damaging and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on MYH2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 598 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). The missense c.1792G>A (p.Glu598Lys) variant in MYH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu598Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submission). Multiple lines of computational evidence (Polyphen - Benign, SIFT - Damaging and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on MYH2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 598 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
PreventionGenetics, part of Exact Sciences	RCV004553319	SCV004716225	likely pathogenic	MYH2-related disorder	2024-04-22	no assertion criteria provided	clinical testing	The MYH2 c.1792G>A variant is predicted to result in the amino acid substitution p.Glu598Lys. This variant was found in multiple members of a family that underwent testing for inclusion body myositis; the family was previously the subject of study demonstrating an autosomal dominant mode of inheritance for inclusion body myositis (internal data; Neville et al. 1992. PubMed ID: 1314344). This variant was also shown to segregate in another family with a chronic inflammatory myopathy and suggestive inclusion body myositis (pedigree LGMD2377 in an unpublished dissertation; https://hdl.handle.net/10161/7169). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.