ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.2896T>C (p.Tyr966His) (rs201180147)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498266 SCV000590463 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The Y966H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 33/125,536 (0.03%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The Y966H 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, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000798904 SCV000938546 uncertain significance Alstrom syndrome 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 966 of the ALMS1 protein (p.Tyr966His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs201180147, ExAC 0.02%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 432709). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825867 SCV000967352 uncertain significance not specified 2018-12-04 criteria provided, single submitter clinical testing The p.Tyr966His variant in ALMS1 has not been previously reported in individuals with hearing loss or Alstrom syndrome, but has been identified in 0.03% (32/127 588) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 432709). Computational p rediction tools and conservation analysis suggest that this variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, the clinical significance of the p.Tyr966His variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4.

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