ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.12425A>G (p.Tyr4142Cys)

gnomAD frequency: 0.00001  dbSNP: rs775032572
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485128 SCV000574391 uncertain significance not provided 2018-03-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The Y4143C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant may be functionally significant at the protein level or the mRNA level. At the protein level, the Y4143C 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. At the mRNA level, in silico splice prediction programs predict that the c.12428 A>G variant creates a strong cryptic splice donor site upstream of the canonical splice donor site in intron 22, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequences of the c.12428 A>G variant cannot be precisely determined.
Genome-Nilou Lab RCV001559282 SCV001781462 uncertain significance Alstrom syndrome 2021-07-14 criteria provided, single submitter clinical testing
Invitae RCV001559282 SCV002148089 uncertain significance Alstrom syndrome 2022-09-01 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 4143 of the ALMS1 protein (p.Tyr4143Cys). This variant is present in population databases (rs775032572, gnomAD 0.002%). 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: 424571). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 RCV001559282 SCV002776578 uncertain significance Alstrom syndrome 2021-09-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV001559282 SCV002081417 uncertain significance Alstrom syndrome 2021-10-13 no assertion criteria provided clinical testing

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