ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.5377_5378delinsAT (p.Ala1793Ile) (rs1131691296)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494037 SCV000581806 uncertain significance not provided 2018-12-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The c.5377_5378delGCinsAT variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.5377_5378delGCinsAT variant causes a deletion of two base pairs and insertion of two different base pairs, which leads to the replacement of an alanine (A) residue with a isoleucine (I) residue at codon position 1793, denoted as A1793I. The A1793I variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and one in silico prediction program predicts this variant likely does not alter the protein structure/function.
Invitae RCV000554375 SCV000631786 uncertain significance Alstrom syndrome 2018-09-19 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 8 of the ALMS1 mRNA (c.5377_5378delinsAT), replacing alanine with isoleucine at codon 1793 of the ALMS1 protein (p.Ala1793Ile). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 429278). 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: "Probably damaging"; 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.
Integrated Genetics/Laboratory Corporation of America RCV001201217 SCV001372304 uncertain significance not specified 2020-06-15 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.5371_5372delinsAT (p.Ala1791Ile), also named as c.5377_5378delinsAT (p.Ala1793Ile) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found as a multinucleotide variant (2-73679028-GC-AT) at a frequency of 6.4e-05 in 280570 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (6.4e-05 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5371_5372delinsAT in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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