ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11584T>C (p.Ser3862Pro)

gnomAD frequency: 0.00058  dbSNP: rs202227966
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481715 SCV000573749 uncertain significance not provided 2024-10-14 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000704301 SCV000833245 uncertain significance Alstrom syndrome 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3863 of the ALMS1 protein (p.Ser3863Pro). This variant is present in population databases (rs202227966, 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: 423980). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825863 SCV000967348 uncertain significance not specified 2018-09-17 criteria provided, single submitter clinical testing The p.Ser3863Pro variant in ALMS1 has not been previously reported in individual s with hearing loss or Alstrom syndrome but has been identified in 0.18% (44/240 14) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 406025). Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Ser3863Pro variant is uncertain. ACMG/AMP Criteria ap plied: BS1_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000825863 SCV002074321 uncertain significance not specified 2022-01-17 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.11581T>C (p.Ser3861Pro, also known as c.11587T>C/p.S3863P in RefSeq) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249020 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.0018 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.11581T>C in individuals affected with Cardiomyopathy or Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with a pathogenic variant has been reported within our laboratory (TTR: c.424G_A, p.Val142Ile), providing supporting evidence for a benign role. Three ClinVar submitters have assessed this variant since 2014: all laboratories classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as of VUS-possibly benign.
Ambry Genetics RCV002356791 SCV002620062 likely benign Cardiovascular phenotype 2021-12-09 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.
Natera, Inc. RCV000704301 SCV002079019 uncertain significance Alstrom syndrome 2021-03-04 no assertion criteria provided clinical testing

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