ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1451G>A (p.Gly484Asp)

gnomAD frequency: 0.00022  dbSNP: rs374663067
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001707718 SCV000618425 uncertain significance not provided 2024-11-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000798208 SCV000937810 uncertain significance Alstrom syndrome 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 485 of the ALMS1 protein (p.Gly485Asp). This variant is present in population databases (rs374663067, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. 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: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Genetic Services Laboratory, University of Chicago RCV000523025 SCV002071643 uncertain significance not specified 2018-10-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV002395252 SCV002696895 likely benign Cardiovascular phenotype 2022-02-25 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV000798208 SCV002782698 uncertain significance Alstrom syndrome 2022-01-10 criteria provided, single submitter clinical testing
Natera, Inc. RCV000798208 SCV002080415 uncertain significance Alstrom syndrome 2021-05-16 no assertion criteria provided clinical testing

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