Submissions for variant NM_001036.6(RYR3):c.3092A>T (p.Lys1031Met)

gnomAD frequency: 0.00006  dbSNP: rs753104655

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551935	SCV000634826	uncertain significance	Epileptic encephalopathy	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1031 of the RYR3 protein (p.Lys1031Met). This variant is present in population databases (rs753104655, gnomAD 0.01%). This missense change has been observed in individual(s) with primary ovarian insufficiency (PMID: 34480478). ClinVar contains an entry for this variant (Variation ID: 461901). 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 RYR3 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.
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano	RCV001270227	SCV001364358	likely pathogenic	Premature ovarian failure	2020-03-02	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198785	SCV001369780	uncertain significance	See cases	2018-12-07	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.