ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.269C>T (p.Pro90Leu) (rs989191437)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478827 SCV000574077 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing The P90L variant has not been publishedas pathogenic or been reported as benign to our knowledge. It is not observed in large population cohorts (Lek et al.,2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P90L variant is a semi-conservativeamino acid substitution, which may impact secondary protein structure as these residues differ in some properties.However, this substitution occurs at a position that is not conserved across species, and in silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly,while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants inALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al.,2014).
Invitae RCV000809783 SCV000949958 uncertain significance Alstrom syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 90 of the ALMS1 protein (p.Pro90Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 424286). 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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