ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.7202G>A (p.Gly2401Glu) (rs373985919)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493524 SCV000582662 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The G2401E variant has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been observed in 4/11542 (0.04%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, this substitution occurs at a position that is not conserved across species and glutamic acid (E) is the wild-type residue at this position in at least one mammalian species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, G2401E 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.
Invitae RCV001245264 SCV001418539 uncertain significance Alstrom syndrome 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 2401 of the ALMS1 protein (p.Gly2401Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs373985919, ExAC 0.03%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429964). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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