ClinVar Miner

Submissions for variant NM_001082486.2(ACD):c.1370C>T (p.Pro457Leu)

gnomAD frequency: 0.00002  dbSNP: rs150387011
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001822510 SCV002065225 uncertain significance not specified 2021-04-16 criteria provided, single submitter clinical testing DNA sequence analysis of the ACD gene demonstrated a sequence change, c.1370C>T, in exon 12 that results in an amino acid change, p.Pro457Leu. This sequence change has been described in gnomAD with a frequency of 0.012% in the African sub-population (dbSNP rs150387011). The p.Pro457Leu change affects a poorly conserved amino acid residue located in a domain of the ACD protein that is not known to be functional. The p.Pro457Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with ACD-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Pro457Leu change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001869758 SCV002306931 uncertain significance Dyskeratosis congenita, autosomal dominant 6 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 543 of the ACD protein (p.Pro543Leu). This variant is present in population databases (rs150387011, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ACD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1337912). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV002397763 SCV002706077 uncertain significance Inborn genetic diseases 2021-08-02 criteria provided, single submitter clinical testing The p.P543L variant (also known as c.1628C>T), located in coding exon 12 of the ACD gene, results from a C to T substitution at nucleotide position 1628. The proline at codon 543 is replaced by leucine, an amino acid with 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.

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