Submissions for variant NM_001082486.2(ACD):c.1168G>A (p.Gly390Arg)

gnomAD frequency: 0.00005  dbSNP: rs553014261

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002395786	SCV002698441	likely benign	Inborn genetic diseases	2021-08-15	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003591862	SCV004280504	uncertain significance	Dyskeratosis congenita, autosomal dominant 6	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 476 of the ACD protein (p.Gly476Arg). This variant is present in population databases (rs553014261, gnomAD 0.04%). 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: 1049325). 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. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355293	SCV001550136	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ACD p.Gly387Arg variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs553014261) and in control databases in 17 of 227966 chromosomes (1 homozygous) at a frequency of 0.00007457 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 8 of 18768 chromosomes (freq: 0.000426), African in 6 of 24118 chromosomes (freq: 0.000249), Latino in 1 of 26912 chromosomes (freq: 0.000037) and European (non-Finnish) in 2 of 107624 chromosomes (freq: 0.000019), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Gly387 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.