ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.12037G>A (p.Gly4013Ser) (rs541576664)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519349 SCV000618446 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing The G4014S variant of uncertain significance in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. The G4014S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species, and serine (S) is the wild-type amino acid at this location in several species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, this variant is observed in 5/66,692 alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) database (Lek et al., 2016).
Fulgent Genetics,Fulgent Genetics RCV000765700 SCV000897051 uncertain significance Alstrom syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000765700 SCV001396693 uncertain significance Alstrom syndrome 2019-07-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 4014 of the ALMS1 protein (p.Gly4014Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs541576664, ExAC 0.01%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449959). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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 RCV000765700 SCV001548513 uncertain significance Alstrom syndrome 2021-03-22 criteria provided, single submitter clinical testing ALMS1 c.12034G>A (rs541576664) is rare (<0.1%) in a large population dataset (gnomAD: 8/250092 total alleles; 0.0032%; 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: 449959). Three bioinformatic tools queried predict that this substitution would be tolerated and the glycine residue at this position is not evolutionarily conserved across the species assessed. Due to insufficient evidence, we consider the clinical significance of c.12034G>A to be uncertain at this time.

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