ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.2662G>A (p.Gly888Arg)

dbSNP: rs797045034
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191072 SCV000245464 likely pathogenic Brain small vessel disease 1 with or without ocular anomalies 2013-09-12 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory de novo in a 27-year-old female with cerebral palsy, cataracts, intellectual disability, and epilepsy
CeGaT Center for Human Genetics Tuebingen RCV001090428 SCV001245972 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
GeneDx RCV001090428 SCV001745402 pathogenic not provided 2019-03-15 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25719457)
3billion RCV000191072 SCV005905028 pathogenic Brain small vessel disease 1 with or without ocular anomalies 2023-11-21 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000209141 /PMID: 25719457). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 26633545). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences RCV004739575 SCV005361940 pathogenic COL4A1-related disorder 2024-06-05 no assertion criteria provided clinical testing The COL4A1 c.2662G>A variant is predicted to result in the amino acid substitution p.Gly888Arg. This variant has been reported in patients with COL4A1 related disorders, and has been documented as a de novo finding (Meuwissen et al. 2015. PubMed ID: 25719457; Coste et al. 2022. PubMed ID: 35150448; https://www.ncbi.nlm.nih.gov/clinvar/variation/209141/). Glycine substitutions in the conserved triple helical domain of this gene are a frequent cause of disease, as seen in this patient (https://www.ncbi.nlm.nih.gov/books/NBK7046/). Of note, one other nucleotide change, causing the same missense alteration (c.2662G>C; p.Gly888Arg) has also been reported as a de novo finding in a patient with a COL4A1-related disease (Giorgio et al. 2015. PubMed ID: 25873210). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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