rs773539041

chr19-15192289-C-Achr19-15192289-C-Gchr19-15192289-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000435.3(NOTCH3):c.350G>T(p.Cys117Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C117Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.77

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 18 ACMG points.

• PS1: Transcript NM_000435.3 (NOTCH3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_000435.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-15192289-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 447837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-15192289-C-A is Pathogenic according to our data. Variant chr19-15192289-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 447838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.350G>T	p.Cys117Phe	missense_variant	4/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.350G>T	p.Cys117Phe	missense_variant	4/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.350G>T	p.Cys117Phe	missense_variant	4/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.347G>T	p.Cys116Phe	missense_variant	4/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451232 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 721190

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 10, 2020	The NOTCH3 c.350G>T; p.Cys117Phe variant (rs773539041), also published as c.428G>T, is reported in the literature in multiple individuals affected with CADASIL (Dichgans 1999, Matsushima 2017, Opherk 2004). This variant is reported in ClinVar (Variation ID: 447838). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (p.Cys117Trp, p.Cys117Tyr, p.Cys117Arg, p.Cys117Ser) have been reported in individuals with CADASIL and are considered pathogenic (Ampuero 2009, Chen 2017, Spinicci 2013, Qin 2019). The cysteine at codon 117 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.974). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Cys117Phe variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Ampuero I et al. On the diagnosis of CADASIL. J Alzheimers Dis. 2009;17(4):787-94. Chen S et al. Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. CNS Neurosci Ther. 2017 Sep;23(9):707-716. doi: 10.1111/cns.12719. Epub 2017 Jul 14. Erratum in: CNS Neurosci Ther. 2018 Dec;24(12):1312-1315. Dichgans M et al. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999 Apr 22;52(7):1361-7. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. doi: 10.1093/brain/awh282. Epub 2004 Sep 13. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Spinicci G et al. Unusual clinical presentations in subjects carrying novel NOTCH3 gene mutations. J Stroke Cerebrovasc Dis. 2013 May;22(4):539-44. doi: 10.1016/j.jstrokecerebrovasdis.2013.02.002. Epub 2013 Mar 1. Qin W et al. Clinical Features of 4 Novel NOTCH3 Mutations of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy in China. Med Sci Monit Basic Res. 2019 Sep 26;25:199-209. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as c.428G>T. 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. -

NOTCH3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 29, 2023

Variant summary: NOTCH3 c.350G>T (p.Cys117Phe) 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. The variant was absent in 226602 control chromosomes (gnomAD). c.350G>T has been reported in the literature in multiple individuals affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) (e.g. Opherk_2004, Matsushima_2017, Wang_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the same amino acid (i.e. C117Y, C117W, C117R) have been reported in individuals with CADASIL/NOTCH3-related disorders, suggesting Cys117 is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 10227618, 27890607, 15364702, 20935329). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.5	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		1.0		Gain of glycosylation at S118 (P = 0.0823);.;
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -12

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

Publications

LitVar

Other links and lift over

dbSNP: rs773539041; hg19: chr19-15303100;