Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000115025 | SCV000192580 | pathogenic | Microcephaly 3, primary, autosomal recessive | 2013-08-15 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000115025 | SCV000916246 | uncertain significance | Microcephaly 3, primary, autosomal recessive | 2017-09-25 | criteria provided, single submitter | clinical testing | The CDK5RAP2 c.524_528delAGGCA (p.Gln175ArgfsTer42) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Gln175ArgfsTer42 variant has been reported in one study in which it was found in a compound heterozygous state with variant affecting a splice acceptor site in a six-year old girl with primary autosomal recessive microcephaly (Tan et al. 2014). The patient was one of triplets and is reported to have severe microcephaly and developmental delay. Her two siblings were unaffected and were not tested for the variant. The p.Gln175ArgfsTer42 variant was also detected in a heterozygous state in the unaffected father. Control data are unavailable for this variant, which is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Due to the potential impact of frameshift variants but limited evidence, the p.Gln175ArgfsTer42 variant is classified as a variant unknown significance but suspicious for pathogenicity for the recessive form of primary microcephaly. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV002515791 | SCV003302602 | pathogenic | not provided | 2023-07-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 127196). This premature translational stop signal has been observed in individual(s) with Seckel Syndrome (PMID: 23726037). This variant is present in population databases (rs587783393, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln175Argfs*42) in the CDK5RAP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDK5RAP2 are known to be pathogenic (PMID: 15793586, 20460369, 26436113). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000115025 | SCV004813159 | pathogenic | Microcephaly 3, primary, autosomal recessive | 2024-02-26 | criteria provided, single submitter | clinical testing | Variant summary: CDK5RAP2 c.524_528delAGGCA (p.Gln175ArgfsX42) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 5.2e-05 in 251102 control chromosomes. c.524_528delAGGCA has been reported in the literature in at-least one individual affected with Primary Autosomal Recessive Microcephaly 3 (example, Tan_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23726037). ClinVar contains an entry for this variant (Variation ID: 127196). Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000115025 | SCV000148934 | pathogenic | Microcephaly 3, primary, autosomal recessive | 2014-04-01 | no assertion criteria provided | literature only |