ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.10777A>G (p.Thr3593Ala) (rs200467041)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000524071 SCV000618291 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The T3593A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in approximately 0.2% of alleles from individuals of African American background in large population cohorts; no homozygous individuals have been reported (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T3593A 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 predicts this variant likely does not alter the protein structure/function. Moreover, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with an ALMS1-related disorder (Stenson et al., 2014).
Invitae RCV000803220 SCV000943082 uncertain significance Alstrom syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 3593 of the ALMS1 protein (p.Thr3593Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs200467041, 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: 449854). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The threonine amino acid residue is 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV001255513 SCV001431950 uncertain significance not specified 2020-08-17 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.10771A>G (p.Thr3591Ala) 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 0.00011 in 248704 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. This frequency is only slight lower than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.0012 vs 0.0014), suggesting this variant may not associate the disease. To our knowledge, no occurrence of c.10771A>G in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.1505G>A, p.Arg502Gln; TTN c.62134C>T, p.Gln20712X), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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