19-15192517-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000435.3(NOTCH3):c.200G>A(p.Cys67Tyr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_000435.3 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.200G>A | p.Cys67Tyr | missense_variant, splice_region_variant | Exon 3 of 33 | ENST00000263388.7 | NP_000426.2 | |
NOTCH3 | XM_005259924.5 | c.200G>A | p.Cys67Tyr | missense_variant, splice_region_variant | Exon 3 of 32 | XP_005259981.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.200G>A | p.Cys67Tyr | missense_variant, splice_region_variant | Exon 3 of 33 | 1 | NM_000435.3 | ENSP00000263388.1 | ||
NOTCH3 | ENST00000601011.1 | c.197G>A | p.Cys66Tyr | missense_variant, splice_region_variant | Exon 3 of 23 | 5 | ENSP00000473138.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 37
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: NOTCH3 c.200G>A (p.Cys67Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 188688 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.200G>A has been reported in the literature in at least one individual affected with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Moon_2003). Other missense variants at this amino acid postion have been submitted as pathogenic/likely pathogenic to ClinVar (p.Cys67Ser; ClinVar Variation ID: 1807398 and p.Cys67Phe; ClinVar Variation ID: 447806) suggesting this codon could be critical for normal function of the protein. These report(s) do not provide unequivocal conclusions about association of the variant with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12589106). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.