Submissions for variant NM_001378615.1(CC2D2A):c.3544T>C (p.Trp1182Arg)

gnomAD frequency: 0.00002  dbSNP: rs386833755

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378831	SCV001576498	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1182 of the CC2D2A protein (p.Trp1182Arg). This variant is present in population databases (rs386833755, gnomAD 0.02%). This missense change has been observed in individual(s) with Joubert syndrome and/or Meckel-Gruber syndrome (PMID: 21068128, 23351400, 36319078). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56307). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335082	SCV004046169	likely pathogenic	CC2D2A-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in two patients with Meckel syndrome (PMID: 21068128, 23351400). The c.3544T>C (p.Trp1182Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/244008) and thus is presumed to be rare. The c.3544T>C (p.Trp1182Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3544T>C (p.Trp1182Arg) variant is classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005031533	SCV005664551	likely pathogenic	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2024-06-21	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049719	SCV000082126	probable-pathogenic	Meckel syndrome, type 6		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723639	SCV001955413	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723639	SCV001970362	likely pathogenic	not provided		no assertion criteria provided	clinical testing