rs1555729477
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000435.3(NOTCH3):c.554G>T(p.Cys185Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C185W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000435.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.554G>T | p.Cys185Phe | missense_variant | 4/33 | ENST00000263388.7 | |
NOTCH3 | XM_005259924.5 | c.554G>T | p.Cys185Phe | missense_variant | 4/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.554G>T | p.Cys185Phe | missense_variant | 4/33 | 1 | NM_000435.3 | P1 | |
NOTCH3 | ENST00000601011.1 | c.551G>T | p.Cys184Phe | missense_variant | 4/23 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 40
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 13, 2022 | This variant has been identified in at least one individual with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at