ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.8456C>T (p.Thr2819Ile) (rs373211307)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000194094 SCV000246363 uncertain significance not specified 2015-07-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726038 SCV000341382 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing
GeneDx RCV000726038 SCV000573403 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing The T2819I variant of uncertain significance in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. T2819I was observed in approximately 0.13% of alleles from individuals of African ancestry in the Exome Aggregation Consortium, yet was not observed at a significant frequency in the 1000 Genomes Project or NHLBI Exome Sequencing Project. The T2819I 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, and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV001066778 SCV001231798 uncertain significance Alstrom syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2819 of the ALMS1 protein (p.Thr2819Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs373211307, 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: 210132). 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.

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