ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.11711G>A (p.Arg3904Gln) (rs201673771)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766766 SCV000530107 uncertain significance not provided 2019-01-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The R3904Q variant has not been published as pathogenic or been reported as benign to our knowledge. The R3904Q variant is a semi-conservative amino 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 glutamine (Q) is the wild-type residue at this position in at least three mammalian species. In silico analysis predicts this variant likely does not alter the protein structure/function. Finally, R3904Q has been observed in 50/66576 (0.08%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Genetic Services Laboratory, University of Chicago RCV000434472 SCV000593116 uncertain significance not specified 2016-08-25 criteria provided, single submitter clinical testing
Invitae RCV000634782 SCV000756125 uncertain significance Alstrom syndrome 2018-02-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 3904 of the ALMS1 protein (p.Arg3904Gln). The arginine residue ismoderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201673771, ExAC 0.08%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 387921). 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: "Probably Damaging"; 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 RCV000434472 SCV000966364 likely benign not specified 2018-07-17 criteria provided, single submitter clinical testing The p.Arg3904Gln variant in ALMS1 is classified as likely benign due to a lack o f conservation across species, including mammals. Of note, golden hamster, mouse and rat have a glutamine (Gln) at this position. It has been identified in 119/ 126668 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org, dbSNP rs201673771). ACMG/AMP Criteria applied: BP4_Str ong, BS1_Supporting.

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