ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11689G>A (p.Gly3897Ser)

gnomAD frequency: 0.00012  dbSNP: rs187887110
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000816500 SCV000957013 uncertain significance Alstrom syndrome 2022-09-12 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3898 of the ALMS1 protein (p.Gly3898Ser). This variant is present in population databases (rs187887110, gnomAD 0.05%). 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: 659481). 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 serine 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.
Ambry Genetics RCV002332685 SCV002630769 uncertain significance Cardiovascular phenotype 2023-06-22 criteria provided, single submitter clinical testing The p.G3898S variant (also known as c.11692G>A), located in coding exon 18 of the ALMS1 gene, results from a G to A substitution at nucleotide position 11692. The glycine at codon 3898 is replaced by serine, an amino acid with similar properties. This variant (referred to as c.11686G>A p.G3896S) was detected in an individual with retinitis pigmentosa who was also homozygous for a suspected causative variant in CDHR1 (Patel N et al. Clin Genet. 2018 Dec;94(6):554-563). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000816500 SCV002814019 uncertain significance Alstrom syndrome 2021-12-08 criteria provided, single submitter clinical testing
New York Genome Center RCV000816500 SCV003925128 uncertain significance Alstrom syndrome 2022-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230598 SCV003928416 uncertain significance not specified 2023-04-18 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.11686G>A (p.Gly3896Ser), also referred to as c.11692G>A, results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249794 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome (4.4e-05 vs 0.0014), allowing no conclusion about variant significance. c.11686G>A has been reported in the literature in an individual affected with retinitis pigmentosa without evidence for causality (Patel_2018). This report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000816500 SCV002079026 uncertain significance Alstrom syndrome 2021-07-26 no assertion criteria provided clinical testing

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