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

Genomes: not found (cov: 32)

Consequence

NOTCH3
NM_000435.3 missense, splice_region

Scores

15
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.68
Variant links:
Genes affected
NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain EGF-like 1 (size 37) in uniprot entity NOTC3_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_000435.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH3NM_000435.3 linkc.200G>A p.Cys67Tyr missense_variant, splice_region_variant Exon 3 of 33 ENST00000263388.7 NP_000426.2 Q9UM47
NOTCH3XM_005259924.5 linkc.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
NOTCH3ENST00000263388.7 linkc.200G>A p.Cys67Tyr missense_variant, splice_region_variant Exon 3 of 33 1 NM_000435.3 ENSP00000263388.1 Q9UM47
NOTCH3ENST00000601011.1 linkc.197G>A p.Cys66Tyr missense_variant, splice_region_variant Exon 3 of 23 5 ENSP00000473138.1 M0R3C9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 13, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.78
T;T
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
1.0
D;D
MetaSVM
Pathogenic
1.3
D
MutationAssessor
Pathogenic
4.7
H;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-9.4
D;.
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.99
MutPred
1.0
Loss of disorder (P = 0.1059);.;
MVP
1.0
MPC
1.7
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.98
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15303328; API