Submissions for variant NM_001845.6(COL4A1):c.4981C>T (p.Arg1661Cys)

dbSNP: rs1555300086

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623377	SCV000742026	likely pathogenic	Inborn genetic diseases	2024-07-25	criteria provided, single submitter	clinical testing	The c.4981C>T (p.R1661C) alteration is located in exon 52 (coding exon 52) of the COL4A1 gene. This alteration results from a C to T substitution at nucleotide position 4981, causing the arginine (R) at amino acid position 1661 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in one individual in an fetal intracranial hemorrhage cohort but clinical details were limited (Coste, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002255156	SCV002526675	likely pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2022-05-04	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_MOD, PS4_SUP, PM2_SUP, PP2, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532839	SCV003511640	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 521435). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1661 of the COL4A1 protein (p.Arg1661Cys).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225100	SCV003921896	uncertain significance	COL4A1 or COL4A2-related cerebral small vessel disease		criteria provided, single submitter	clinical testing	- Variant is absent from gnomAD (both v2 and v3). - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). Additional information: - Dominant negative and loss of function are likely mechanisms of disease in this gene and are associated with COL4A1-related disorders. Missense variants affecting the glycine of the triple helix of collagen protiens typically exert a dominant-negative effect however, functional studies for this gene are currently lacking (PMID: 16159887). - This gene is associated with autosomal dominant disease. - The condition associated with this gene has incomplete penetrance (PMID: 30413629, PMID:21625620). - Variant is predicted to result in a missense amino acid change from arginine to cysteine. - This variant is heterozygous. - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). - Variant is located in the annotated C4 domain (DECIPHER). - No comparable missense variants have previous evidence for pathogenicity. - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in an individual with features including seizures, microcephaly and oligohydramnios (ClinVar). - No published segregation evidence has been identified for this variant. - No published functional evidence has been identified for this variant.