Submissions for variant NM_001845.6(COL4A1):c.3832G>A (p.Gly1278Ser)

gnomAD frequency: 0.00001  dbSNP: rs757453900

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002246243	SCV001430782	uncertain significance	Brain small vessel disease 1 with or without ocular anomalies	2020-05-29	criteria provided, single submitter	research	The homoygous p.Gly1278Ser variant in COL4A1 was identified by our study in 2 siblings with brain small vessel disease with or without ocular anomalies. These siblings, along with an additional homozygous, affected family member are reported in the literature (PMID: 32042920). This variant has been identified in 0.0045% (3/66584) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs757453900). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_supporting, PP3, PP1 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002568742	SCV003519649	likely pathogenic	not provided	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1278 of the COL4A1 protein (p.Gly1278Ser). This variant is present in population databases (rs757453900, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive small vessel brain disease with periventricular leukoencephalopathy and ocular defects (PMID: 32042920). ClinVar contains an entry for this variant (Variation ID: 977158). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the triple helix domain of COL4A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A1 variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). 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.