Submissions for variant NM_001082486.2(ACD):c.446A>G (p.Tyr149Cys)

gnomAD frequency: 0.00005  dbSNP: rs200909340

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001927357	SCV002158180	uncertain significance	Dyskeratosis congenita, autosomal dominant 6	2024-01-13	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 235 of the ACD protein (p.Tyr235Cys). This variant is present in population databases (rs200909340, gnomAD 0.05%). 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: 1394247). 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.
Ambry Genetics	RCV002370465	SCV002667954	uncertain significance	Inborn genetic diseases	2021-07-25	criteria provided, single submitter	clinical testing	The p.Y235C variant (also known as c.704A>G), located in coding exon 5 of the ACD gene, results from an A to G substitution at nucleotide position 704. The tyrosine at codon 235 is replaced by cysteine, an amino acid with highly dissimilar 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003151362	SCV005090230	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004793577	SCV005411338	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BP4
Genetic Services Laboratory, University of Chicago	RCV003151362	SCV003840125	uncertain significance	not specified	2022-04-28	no assertion criteria provided	clinical testing	DNA sequence analysis of the ACD gene demonstrated a sequence change, c.446A>G, in exon 5 that results in an amino acid change, p.Tyr149Cys. This sequence change has been described in the gnomAD database with a frequency of 0.045% in the East Asian subpopulation (dbSNP rs200909340). The p.Tyr149Cys change affects a moderately conserved amino acid residue located in a domain of the ACD protein that is not known to be functional. The p.Tyr149Cys 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 individuals with ACD-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Tyr149Cys change remains unknown at this time.