ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.12047G>A (p.Gly4016Asp) (rs200462734)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413866 SCV000491842 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The G4016D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the G4016D 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.
Invitae RCV000477216 SCV000541334 uncertain significance Alstrom syndrome 2016-11-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 4016 of the ALMS1 protein (p.Gly4016Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs200462734, ExAC 0.04%) but has not been reported in the literature in individuals with an 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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