ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.4207A>G (p.Thr1403Ala) (rs199649563)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229674 SCV000290085 uncertain significance Alstrom syndrome 2016-01-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1403 of the ALMS1 protein (p.Thr1403Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs199649563, ExAC 0.07%) but has not been reported in the literature in individuals with a ALMS1-related disease. The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, 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: "Possibly damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480638 SCV000573176 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The T1403A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1403A 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 where alanine is the wild type in at least two species. Finally, in silico analysis predicts this variant likely does not alter the protein structure/function.

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