ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.11587T>C (p.Ser3863Pro) (rs202227966)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481715 SCV000573749 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The S3863P variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in other individuals referred for cardiac genetic testing at GeneDx; however, these individuals all harbored additional variants in other genes, and a second pathogenic variant in the ALMS1 gene was not identified. This variant has also been observed in 44/24014 (0.18%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). Additionally, 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). Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, S3863P 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 RCV000704301 SCV000833245 uncertain significance Alstrom syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 3863 of the ALMS1 protein (p.Ser3863Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs202227966, ExAC 0.2%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 423980). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825863 SCV000967348 uncertain significance not specified 2018-09-17 criteria provided, single submitter clinical testing The p.Ser3863Pro variant in ALMS1 has not been previously reported in individual s with hearing loss or Alstrom syndrome but has been identified in 0.18% (44/240 14) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 406025). Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Ser3863Pro variant is uncertain. ACMG/AMP Criteria ap plied: BS1_Supporting.

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