ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1886G>A (p.Gly629Asp) (rs531859344)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000697141 SCV000825737 uncertain significance Alstrom syndrome 2019-07-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 630 of the ALMS1 protein (p.Gly630Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs531859344, ExAC 0.01%). This variant has not been reported in the literature in individuals with ALMS1-related disease. 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.
Johns Hopkins Genomics, Johns Hopkins University RCV000697141 SCV001548515 uncertain significance Alstrom syndrome 2021-03-22 criteria provided, single submitter clinical testing ALMS1 c.1883G>A (rs531859344) is rare (<0.1%) in a large population dataset (gnomAD: 5/280468 total alleles; 0.0018%; no homozygotes). This ALMS1 variant has not been reported in the literature to our knowledge, but there is an entry for this variant in ClinVar (Variation ID: 575048). Of three bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while two predict that it would be tolerated. The glycine residue at this position is not highly evolutionarily conserved among the species assessed. Due to insufficient evidence, we consider the clinical significance of c.1883G>A to be uncertain at this time.

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