Submissions for variant NM_013444.4(UBQLN2):c.808C>T (p.Arg270Cys)

gnomAD frequency: 0.00001  dbSNP: rs1330837640

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001167822	SCV001330359	uncertain significance	Amyotrophic lateral sclerosis type 15	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001167822	SCV004641416	uncertain significance	Amyotrophic lateral sclerosis type 15	2023-08-07	criteria provided, single submitter	clinical testing	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. 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 UBQLN2 protein function. ClinVar contains an entry for this variant (Variation ID: 913947). This variant has not been reported in the literature in individuals affected with UBQLN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 270 of the UBQLN2 protein (p.Arg270Cys).
Neuberg Centre For Genomic Medicine, NCGM	RCV001167822	SCV005374772	uncertain significance	Amyotrophic lateral sclerosis type 15	2023-06-02	criteria provided, single submitter	clinical testing	The missense variant c.808C>T(p.Arg270Cys) in UBQLN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance (VUS). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Arg270Cys in UBQLN2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 270 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). The observed variant has also been detected in heterozygous state in ID: 30507401448. No significant variant in UBQLN2 gene has been detected in; ID: 30507401447 and ; ID: 30507401446.