ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.5830C>T (p.Arg1944Cys) (rs370398704)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430402 SCV000536633 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The R1944C 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 R1944C 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 suggests that this variant likely does not alter the protein structure/function.
Invitae RCV000477620 SCV000541357 uncertain significance Alstrom syndrome 2017-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1944 of the ALMS1 protein (p.Arg1944Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs370398704, ExAC 0.03%) but has not been reported in the literature in individuals with an ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 393252). 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: "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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