ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.2068A>G (p.Thr690Ala) (rs201804994)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234517 SCV000290075 uncertain significance Alstrom syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 690 of the ALMS1 protein (p.Thr690Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs201804994, ExAC 0.03%) but has not been reported in the literature in individuals with a ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 240985). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000435375 SCV000532509 uncertain significance not specified 2017-10-04 criteria provided, single submitter clinical testing The T690A variant of uncertain significance in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. The T690A variant is observed in 65/126072 (0.05%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). 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. Additionally, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014). Nonetheless, the T690A 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.

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