ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.2538C>G (p.Asp846Glu) (rs77517267)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489305 SCV000576824 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing The D846E variant of uncertain significance in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 53/24,006 (0.2%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). D846E is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, 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 RCV000634784 SCV000756127 uncertain significance Alstrom syndrome 2017-12-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 846 of the ALMS1 protein (p.Asp846Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs77517267, 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: 426397). 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: "Deleterious"; PP2: "Benign", 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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