ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11953A>G (p.Ile3985Val)

gnomAD frequency: 0.00014  dbSNP: rs201728850
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000705168 SCV000834153 uncertain significance Alstrom syndrome 2022-11-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3986 of the ALMS1 protein (p.Ile3986Val). This variant is present in population databases (rs201728850, gnomAD 0.2%). 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: 581362). 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 valine 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.
Fulgent Genetics, Fulgent Genetics RCV000705168 SCV000897049 uncertain significance Alstrom syndrome 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001195324 SCV001365667 likely benign not specified 2019-10-04 criteria provided, single submitter clinical testing The p.Ile3986Val variant in ALMS1 is classified as likely benign because it has been identified in 0.1% (59/35436) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1_Supporting, BP4.
Genome-Nilou Lab RCV000705168 SCV001652731 likely benign Alstrom syndrome 2021-05-18 criteria provided, single submitter clinical testing
GeneDx RCV001560085 SCV001782424 uncertain significance not provided 2023-10-17 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
Genetic Services Laboratory, University of Chicago RCV001195324 SCV002066449 uncertain significance not specified 2019-05-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002334381 SCV002641112 likely benign Cardiovascular phenotype 2019-10-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
New York Genome Center RCV000705168 SCV003925100 uncertain significance Alstrom syndrome 2021-12-09 criteria provided, single submitter clinical testing The heterozygous c.11953A>G (p.Ile3986Val) missense variant identified in the ALMS1 gene has not been reported in affected individuals in the literature. The variant has 0.0003620 allele frequency in the gnomAD (v2.1.1 and v3.1.2) database (102 out of 281762 heterozygous alleles, no homozygotes). This variant is reported as both a Variant of uncertain significance and likely benign associated with Alstrom syndrome in the ClinVar database (Variation ID: 581362). The variant affects a weakly conserved residue (Ile3986) of ALMS1 protein and is predicted neutral by multiple in silico prediction tools (CADD score = 6.015, REVEL score= 0.243). Based on the available evidence, the heterozygous c.11953A>G (p.Ile3986Val) missense variant identified in the ALMS1 gene is reported as a Variant of Uncertain Significance.
Natera, Inc. RCV000705168 SCV001459608 likely benign Alstrom syndrome 2020-04-23 no assertion criteria provided clinical testing

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