ClinVar Miner

Submissions for variant NM_001082486.2(ACD):c.67C>A (p.Pro23Thr)

gnomAD frequency: 0.00001  dbSNP: rs1039048796
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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 RCV001822525 SCV002065264 uncertain significance not specified 2021-05-03 criteria provided, single submitter clinical testing DNA sequence analysis of the ACD gene demonstrated a sequence change, c.67C>A, in exon 1 that results in an amino acid change, p.Pro23Thr. This sequence change has been described in gnomAD with a frequency of 0.0009% in the Non-Finnish European sub-population (dbSNP rs1039048796). The p.Pro23Thr change affects a moderately conserved amino acid residue located in a domain of the ACD protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro23Thr substitution. 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.Pro23Thr change remains unknown at this time.
Ambry Genetics RCV002324211 SCV002606904 uncertain significance Inborn genetic diseases 2021-09-04 criteria provided, single submitter clinical testing The p.P109T variant (also known as c.325C>A), located in coding exon 1 of the ACD gene, results from a C to A substitution at nucleotide position 325. The proline at codon 109 is replaced by threonine, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003754925 SCV004509838 uncertain significance Dyskeratosis congenita, autosomal dominant 6 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 109 of the ACD protein (p.Pro109Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1337927). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACD protein function with a negative predictive value of 80%. 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.

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