ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.11258A>G (p.Asn3753Ser) (rs199917289)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523193 SCV000618740 uncertain significance not provided 2019-01-02 criteria provided, single submitter clinical testing The N3753S 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 42/23,950 (0.1%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The N3753S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, 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). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001242906 SCV001416026 uncertain significance Alstrom syndrome 2019-08-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 3753 of the ALMS1 protein (p.Asn3753Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs199917289, ExAC 0.2%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 450189). 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: "Tolerated"; 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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