Submissions for variant NM_001082486.2(ACD):c.1052G>A (p.Arg351His)

gnomAD frequency: 0.00001  dbSNP: rs370293582

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206245	SCV001377543	uncertain significance	Dyskeratosis congenita, autosomal dominant 6	2022-09-09	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 937272). This variant has not been reported in the literature in individuals affected with ACD-related conditions. This variant is present in population databases (rs370293582, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 437 of the ACD protein (p.Arg437His). 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	RCV002379781	SCV002690015	uncertain significance	Inborn genetic diseases	2023-10-28	criteria provided, single submitter	clinical testing	The p.R437H variant (also known as c.1310G>A), located in coding exon 10 of the ACD gene, results from a G to A substitution at nucleotide position 1310. The arginine at codon 437 is replaced by histidine, 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.
Genetic Services Laboratory, University of Chicago	RCV003151289	SCV003840014	uncertain significance	not specified	2022-12-08	no assertion criteria provided	clinical testing	DNA sequence analysis of the ACD gene demonstrated a sequence change, c.1052G>A, in exon 10 that results in an amino acid change, p.Arg351His. This sequence change does not appear to have been previously described in individuals with ACD-related disorders. This sequence change has been described in the gnomAD database with a global frequency of 0.0012% (dbSNP rs370293582). The p.Arg351His 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.Arg351His substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg351His change remains unknown at this time.