Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002510405 | SCV002819711 | likely pathogenic | Porencephaly 2 | 2022-12-21 | criteria provided, single submitter | clinical testing | Variant summary: COL4A2 c.520_523delinsACA (p.Leu174ThrfsX72) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant was absent in 247178 control chromosomes (gnomAD). To our knowledge, no occurrence of c.520_523delinsACA in individuals affected with Porencephaly 2 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Clinical Genomics Laboratory, |
RCV005051977 | SCV005685510 | uncertain significance | COL4A2-related cerebral small vessel disease | 2024-06-07 | criteria provided, single submitter | clinical testing | The COL4A2 c.520_523delinsACA (p.Leu174Thrfs*72) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline likely pathogenic variant by one submitter. This variant is only observed on 2/1,611,862 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant (called as three individual variants: 13-110429925-C-CA, 13-110429930-C-A, 13-110429927-CTG-C). This variant causes a frameshift by deleting four nucleotides and inserting three nucleotides, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Other frameshift and nonsense-inducing COL4A2 variants have been described as likely pathogenic in ClinVar and at least one family with a frameshift COL4A2 variant showed variable expressivity from severe hydrocephalus to mild intellectually disability and normal brain MRI (Verbeek E et al., PMID: 22333902). However, due to uncertainty regarding the pathogenicity of nonsense-inducing COL4A2 variants, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. |