ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.1454G>A (p.Gly485Asp) (rs374663067)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523025 SCV000618425 uncertain significance not specified 2017-05-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The G485D variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in one other individual referred for cardiomyopathy genetic testing at GeneDx, although a second variant in the ALMS1 gene was not reported. This variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G485D 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. Nevertheless, 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.
Integrated Genetics/Laboratory Corporation of America RCV000523025 SCV000864107 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing Variant summary: The ALMS1 c.1451G>A (p.Gly484Asp alternative name c.1454G>A) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 2/4 in silico tools (SNPs&GO not captured due to low reliability index). This variant was found in 14/120270 control chromosomes from ExAC, predominantly observed in the African subpopulation at a frequency of 0.001327 (13/9798). This frequency is slightly lower than the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361). No homozygotes have been reported in ExAC. It may be a rare polymorphism in African population, however no other supporting evidences are present at this time. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. One internal sample carrying this variant also carries a pathogenic variant SCN5A c.2440C>T (p.Arg814Trp). Because of the absence of sufficient clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000798208 SCV000937810 uncertain significance Alstrom syndrome 2019-07-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 485 of the ALMS1 protein (p.Gly485Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs374663067, ExAC 0.1%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 449942). 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 aspartic 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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