rs376046941

Positions:

• chr19-15185632-C-A
• chr19-15185632-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BS2_Supporting

The NM_000435.3(NOTCH3):​c.1999G>T​(p.Gly667Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G667D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.73

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 19-15185632-C-A is Pathogenic according to our data. Variant chr19-15185632-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447805.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr19-15185632-C-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.1999G>T	p.Gly667Cys	missense_variant	13/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.1999G>T	p.Gly667Cys	missense_variant	13/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.1999G>T	p.Gly667Cys	missense_variant	13/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.1996G>T	p.Gly666Cys	missense_variant	13/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250816 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461360 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726944

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 28, 2022	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 667 of the NOTCH3 protein (p.Gly667Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL) (PMID: 22664156). ClinVar contains an entry for this variant (Variation ID: 447805). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 22, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.88	L;.
MutationTaster	Benign	0.75	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.12	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.67	P;.
Vest4		0.81
MVP		1.0
MPC		1.0
ClinPred		0.86	D
GERP RS		4.0
Varity_R		0.20
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs376046941; hg19: chr19-15296443;