ClinVar Miner

Submissions for variant NM_001082486.2(ACD):c.124G>A (p.Val42Ile)

gnomAD frequency: 0.00001  dbSNP: rs758513965
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001373877 SCV001570609 uncertain significance Dyskeratosis congenita, autosomal dominant 6 2022-12-06 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1063974). This variant has not been reported in the literature in individuals affected with ACD-related conditions. This variant is present in population databases (rs758513965, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 128 of the ACD protein (p.Val128Ile).
Genetic Services Laboratory, University of Chicago RCV001820079 SCV002068489 uncertain significance not specified 2018-02-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV002357276 SCV002623249 uncertain significance Inborn genetic diseases 2023-09-06 criteria provided, single submitter clinical testing The p.V128I variant (also known as c.382G>A), located in coding exon 2 of the ACD gene, results from a G to A substitution at nucleotide position 382. The valine at codon 128 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001820079 SCV004241102 uncertain significance not specified 2023-12-15 criteria provided, single submitter clinical testing Variant summary: ACD c.124G>A (p.Val42Ile) results in a conservative amino acid change located in the Shelterin complex subunit TPP1/Est3 (IPR019437) of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 232550 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.124G>A in individuals affected with Dyskeratosis Congenita, Autosomal Dominant 6 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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