ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.8284C>G (p.Pro2762Ala) (rs369650940)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489619 SCV000576710 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing The P2762A variant of uncertain significance in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 19/23,986 (0.08%) alleles from individuals of African ancestry in large population cohorts, though no individuals were reported to be homozygous (Lek et al., 2016). The P2762A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Additionally, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014).
Invitae RCV000526705 SCV000631807 uncertain significance Alstrom syndrome 2017-06-20 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 2762 of the ALMS1 protein (p.Pro2762Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs369650940, ExAC 0.05%). This variant has not been reported in the literature in individuals with a ALMS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on ALMS1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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