rs1064794216

Positions:

• chr19-15180217-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000263388.7(NOTCH3):​c.3182G>A​(p.Cys1061Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOTCH3 ENST00000263388.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.58

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a disulfide_bond (size 15) in uniprot entity NOTC3_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in ENST00000263388.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 19-15180217-C-T is Pathogenic according to our data. Variant chr19-15180217-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15180217-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.3182G>A	p.Cys1061Tyr	missense_variant	20/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.3026G>A	p.Cys1009Tyr	missense_variant	19/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.3182G>A	p.Cys1061Tyr	missense_variant	20/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1	c.3023G>A	p.Cys1008Tyr	missense_variant	19/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461620 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1061 of the NOTCH3 protein (p.Cys1061Tyr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys1061 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 33942994), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 419978). This missense change has been observed in individuals with clinical features of CADASIL (PMID: 22639698, 31443546; Invitae). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24844136, 22639698, 31443546) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2022	This variant has been identified in at least one individual with clinical features associated with 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2023	PP2, PP3, PM1, PM2, PM5, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.5	D
MutationAssessor	Pathogenic	4.9	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.6	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.99		Gain of phosphorylation at C1061 (P = 0.0267);.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.91
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

LitVar

Other links and lift over

dbSNP: rs1064794216; hg19: chr19-15291028;