ClinVar Miner

Submissions for variant NM_001194998.2(CEP152):c.794A>C (p.Gln265Pro)

gnomAD frequency: 0.00001  dbSNP: rs267606717
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000000072 SCV000192745 likely pathogenic Microcephaly 9, primary, autosomal recessive 2014-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000413650 SCV000491286 likely pathogenic not provided 2022-05-31 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20598275, 23456457, 21668957, 30086807)
Fulgent Genetics, Fulgent Genetics RCV000763360 SCV000894050 pathogenic Seckel syndrome 5; Microcephaly 9, primary, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000778440 SCV000914686 likely pathogenic CEP152-related disorder 2017-09-01 criteria provided, single submitter clinical testing The CEP152 c.794A>C (p.Gln265Pro) missense variant has been reported in one study in which it was found in three individuals with microcephaly, with head circumferences between five and seven standard deviations below the mean, including in two individuals in a homozygous state and in one individual in a compound heterozygous state with a null variant on the second allele (Guernsey et al. 2010). The p.Gln265Pro variant was found in a heterozygous state in each of the unaffected parents of the affected individuals. The p.Gln265Pro variant was absent from 496 control chromosomes including 310 local Maritime control chromosomes and 186 European control chromosomes from the Centre d'Etude du Polymorphisme Humain (CEPH) (Guernsey et al. 2010). The variant is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Transfection of the variant protein into human U2OS osteosarcoma-derived cells did not affect localization, with the variant protein being found in the centrosomes similarly to wild type. However, the Gln265 residue is highly conserved among vertebrates and is predicted to fall in a coiled-coiled region predicted to be disrupted by substitution of a proline residue (Guernsey et al. 2010). Based on the evidence, the c.794A>C (p.Gln265Pro) variant is classified as likely pathogenic for CEP152-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV000413650 SCV004297264 likely pathogenic not provided 2022-12-03 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CEP152 protein function. ClinVar contains an entry for this variant (Variation ID: 55). This missense change has been observed in individual(s) with primary microcephaly (PMID: 20598275). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs267606717, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 265 of the CEP152 protein (p.Gln265Pro).
OMIM RCV000000072 SCV000020215 pathogenic Microcephaly 9, primary, autosomal recessive 2010-07-09 no assertion criteria provided literature only

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