Submissions for variant NM_006642.5(SDCCAG8):c.237T>A (p.Asp79Glu)

gnomAD frequency: 0.00038  dbSNP: rs146474568

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000310366	SCV000356797	uncertain significance	Senior-Loken syndrome 7	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000365007	SCV000356798	uncertain significance	Bardet-Biedl syndrome 16	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532918	SCV000655039	uncertain significance	Senior-Loken syndrome 7; Bardet-Biedl syndrome 16	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 79 of the SDCCAG8 protein (p.Asp79Glu). This variant is present in population databases (rs146474568, gnomAD 0.07%). This missense change has been observed in individual(s) with a nephronophthisis-associated ciliopathy and/or inherited retinal disorder (PMID: 23188109, 32483926). ClinVar contains an entry for this variant (Variation ID: 296904). 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 SDCCAG8 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.
PreventionGenetics, part of Exact Sciences	RCV004537661	SCV004117784	uncertain significance	SDCCAG8-related disorder	2023-12-05	criteria provided, single submitter	clinical testing	The SDCCAG8 c.237T>A variant is predicted to result in the amino acid substitution p.Asp79Glu. This variant was reported in an individual with nephronophthisis-associated ciliopathies; however, a second SDCCAG8 variant was not identified (Halbritter et al. 2012. PubMed ID: 23188109, supplementary table 5). Additionally, this variant was identified as a variant of uncertain significance in a large cohort of individuals with retinal disorders (Dineiro et al. 2020. PubMed ID: 32483926). This variant was also described in a large cohort of individuals with Bardet-Biedl syndrome; however, this individual harbored a homozygous BBS9 deletion (Nasser et al. 2022. PubMed ID: 35886001, supplementary data). This variant is reported in 0.072% of alleles in individuals of South Asian descent in gnomAD, which is likely too common to be a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.