Submissions for variant NM_005184.4(CALM3):c.421G>A (p.Glu141Lys)

dbSNP: rs1599759598

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860538	SCV002170912	pathogenic	Long QT syndrome 1	2021-07-07	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu141 amino acid residue in CALM3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects CALM3 protein function (PMID: 31454269). ClinVar contains an entry for this variant (Variation ID: 812678). This variant has been observed in individual(s) with long QT syndrome (PMID: 31454269). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 141 of the CALM3 protein (p.Glu141Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001003484	SCV002769517	pathogenic	Long QT syndrome 16	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a reported mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0508 - Variant affects last nucleotide of an exon however, conservation and in silico predictions for abnormal splicing are conflicting (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. p.(Glu141Gly) has been reported likely pathogenic (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. Seen 2x in patients with long QT syndrome, including 1 de novo (PMID: 31454269). (P) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated reduced Ca2+ binding (PMID: 31454269). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
OMIM	RCV001003484	SCV001161780	pathogenic	Long QT syndrome 16	2020-02-21	no assertion criteria provided	literature only