ClinVar Miner

Submissions for variant NM_001080522.2(CC2D2A):c.4667A>T (p.Asp1556Val) (rs201502401)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000286210 SCV000858007 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000286210 SCV000329215 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing The D1556V variant in the CC2D2A gene has been reported previously in multiple unrelated individuals with Joubert syndrome and related disorders who were heterozygous for a second deleterious variant on the other allele, and was identified in a single patient with no second detectable variant (Mougou-Zerelli et al., 2009; Bachmann-Gagescu et al., 2012; Srour et al., 2015). The D1556V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is observed in 47/125754 (0.037%) alleles from individuals of European background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret D1556V as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000287733 SCV000448084 uncertain significance Meckel-Gruber syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778102 SCV000448085 pathogenic CC2D2A-Related Disorders 2018-05-07 criteria provided, single submitter clinical testing The CC2D2A c.4667A>T (p.Asp1556Val) missense variant has been reported in six studies in which it is found in 20 individuals with Joubert syndrome, including in 19 in a compound heterozygous state (including two sibling pairs) and in one individual in a heterozygous state in whom a second variant was not found (Mougou-Zerelli et. al. 2009; Bachmann-Gagescu et. al. 2012; Srour et. al. 2012a; Srour et. al. 2012b; Srour et. al. 2015; Bachmann-Gagescu et. al. 2015). The variant was also found in a heterozygous state in one unaffected individual. The variant has not been reported in individuals with Meckel syndrome. The p.Asp1556Val variant was absent from 2376 control chromosomes and is reported at a frequency of 0.00027 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Asp1556 residue is highly conserved. Based on the evidence, the p.Asp1556Val variant is classified as pathogenic for CC2D2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000474430 SCV000553241 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 1556 of the CC2D2A protein (p.Asp1556Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs201502401, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic or likely pathogenic variant in several individuals affected with Joubert syndrome (PMID: 22241855, 26092869, 26477546, Invitae database). This finding is consistent with autosomal recessive inheritance, and strongly suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 217607). This variant has also been reported in many individuals affected with Joubert syndrome where a second variant was not detected, or the second variant has not been firmly established as pathogenic or likely pathogenic (PMID: 19777577, 22241855, 22425360, 23012439, 26092869, 26477546). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000347415 SCV000712657 pathogenic Joubert syndrome 2016-11-14 criteria provided, single submitter clinical testing The p.Asp1556Val variant in CC2D2A has been reported in at least 7 individuals w ith Joubert syndrome in the compound heterozygous state (Mougou-Zerelli 2009, Ba chmann-Gagescu 2015). This variant was also detected in 0.03% (18/65,952) of Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs201502401). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a recessive ca rrier frequency. Biallelic mutations in CC2D2A have been associated with Joubert syndrome. In summary, this variant meets criteria to be classified as pathogen ic for Joubert syndrome in an autosomal recessive manner based upon case observa tions and low frequency in controls.
Laboratory of Molecular Genetics (Pr. Bezieau's lab),CHU de Nantes RCV000286210 SCV000778197 pathogenic not provided 2016-05-24 no assertion criteria provided clinical testing
UW Hindbrain Malformation Research Program,University of Washington RCV000201706 SCV000256350 pathogenic Joubert syndrome 9 2015-02-23 criteria provided, single submitter research

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