Submissions for variant NM_001082486.2(ACD):c.1004G>A (p.Arg335His)

gnomAD frequency: 0.00002  dbSNP: rs774558672

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001938227	SCV002194273	uncertain significance	Dyskeratosis congenita, autosomal dominant 6	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 421 of the ACD protein (p.Arg421His). This variant is present in population databases (rs774558672, gnomAD 0.03%). 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: 1417229). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002236188	SCV002511588	uncertain significance	not specified	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: ACD c.1004G>A (p.Arg335His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 247022 control chromosomes (gnomAD). c.1262G>A has been reported in the literature in a family with Retinitis pigmentosa, however the variant did not segregate with disease (example: Chen_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publication has been ascertained in the context of this evaluation (PMID: 29843741). One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002449591	SCV002680605	likely benign	Inborn genetic diseases	2021-07-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.