ClinVar Miner

Submissions for variant NM_001378615.1(CC2D2A):c.541G>A (p.Val181Ile)

gnomAD frequency: 0.00004  dbSNP: rs745646755
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001243261 SCV001416407 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-02-23 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 181 of the CC2D2A protein (p.Val181Ile). This variant is present in population databases (rs745646755, gnomAD 0.03%). 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: 968182). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV003339561 SCV004047000 uncertain significance Meckel syndrome, type 6 criteria provided, single submitter clinical testing The missense variant in c.541G>A (p.Val181Ile) in CC2D2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val181Ile variant is reported with the allele frequency of 0.007004% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as uncertain significance. The amino acid Val at position 181 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Val181Ile in CC2D2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Uncertain Significance.

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