ClinVar Miner

Submissions for variant NM_018834.6(MATR3):c.2521C>T (p.Arg841Cys) (rs781050726)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000651345 SCV000453187 benign Amyotrophic lateral sclerosis 21 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000651345 SCV000773196 uncertain significance Amyotrophic lateral sclerosis 21 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 841 of the MATR3 protein (p.Arg841Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs781050726, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual with spinal-onset amyotrophic lateral sclerosis of pseudopolyneuritic type (PMID: 29525178). ClinVar contains an entry for this variant (Variation ID: 351143). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. comment

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