ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.8309C>T (p.Ser2770Phe) (rs1060500037)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463093 SCV000541344 uncertain significance Alstrom syndrome 2016-05-11 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 2770 of the ALMS1 protein (p.Ser2770Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ALMS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; Polyphen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The p.Phe2770 amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000498122 SCV000590285 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The S2770F variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S2770F 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 is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, S2770F is also classified as a variant of uncertain significance in ClinVar by another clinical laboratory (ClinVar SCV000541344.1; Landrum et al., 2016).

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