ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11939C>T (p.Thr3980Ile) (rs200568988)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485283 SCV000573415 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The T3981I variant has not been published as pathogenic or been reported as benign to our knowledge. The Exome Aggregation Consortium (ExAC) reports T3981I was observed in 11/9,858 alleles from individuals of African background (Lek et al., 2016). The T3981I 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 Isoleucine is the wild-type amino acid at this position in multiple species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV001040891 SCV001204482 uncertain significance Alstrom syndrome 2019-11-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 3981 of the ALMS1 protein (p.Thr3981Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs200568988, ExAC 0.1%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423689). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264558 SCV001442767 uncertain significance not specified 2020-10-01 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.11936C>T (p.Thr3979Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250394 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (8.4e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.11936C>T in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both citing the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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