Submissions for variant NM_001378615.1(CC2D2A):c.1484G>A (p.Arg495His)

gnomAD frequency: 0.00009  dbSNP: rs373906628

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478789	SCV000570015	uncertain significance	not specified	2017-05-31	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CC2D2A gene. The R495H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and the 1000 Genomes Project reports it was observed in 0.2% of alleles from individuals of East Asian background. The R495H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the R495H variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000729708	SCV000857394	uncertain significance	not provided	2017-10-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001149498	SCV001310454	uncertain significance	Joubert syndrome 9	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	RCV001149499	SCV001310455	uncertain significance	Meckel syndrome, type 6	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	RCV001248595	SCV001422094	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-09-01	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 495 of the CC2D2A protein (p.Arg495His). This variant is present in population databases (rs373906628, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 420965). 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 expected to disrupt CC2D2A 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.
Fulgent Genetics, Fulgent Genetics	RCV005027549	SCV005660549	uncertain significance	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2024-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732896	SCV005347108	uncertain significance	CC2D2A-related disorder	2024-07-14	no assertion criteria provided	clinical testing	The CC2D2A c.1484G>A variant is predicted to result in the amino acid substitution p.Arg495His. This variant was reported in the compound heterozgous state in an infant with Joubert syndrome (Table S8, Fu et al 2022. PubMed ID: 36307859). This variant is reported in 0.035% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.