rs1555300086
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_001845.6(COL4A1):c.4981C>T(p.Arg1661Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1661H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001845.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A1 | NM_001845.6 | c.4981C>T | p.Arg1661Cys | missense_variant | 52/52 | ENST00000375820.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A1 | ENST00000375820.10 | c.4981C>T | p.Arg1661Cys | missense_variant | 52/52 | 1 | NM_001845.6 | P1 | |
COL4A1 | ENST00000650424.1 | c.1132C>T | p.Arg378Cys | missense_variant | 10/10 | ||||
COL4A1 | ENST00000649720.1 | n.1149C>T | non_coding_transcript_exon_variant | 7/7 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461650Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727134
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Brain small vessel disease 1 with or without ocular anomalies Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 04, 2022 | This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_MOD, PS4_SUP, PM2_SUP, PP2, PP3 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2022 | 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). - |
COL4A1 or COL4A2-related cerebral small vessel disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | - | - 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at