ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.3293A>G (p.Tyr1098Cys) (rs201816596)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418543 SCV000533094 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The Y1098C variant has not been published as pathogenic or been reported as benign to our knowledge. The Y1098C 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. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the Y1098C variant is observed in 0.23-0.45% alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000560896 SCV000631775 uncertain significance Alstrom syndrome 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1098 of the ALMS1 protein (p.Tyr1098Cys). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs201816596, ExAC 0.2%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 390302). 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: "Deleterious"; 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.

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