9-136515323-C-T

Position:

chr9-136515323-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_017617.5(NOTCH1):c.1981G>A(p.Gly661Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000554 in 1,613,026 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3O:1

Conservation

PhyloP100: 3.97

Variant links:

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 links:

LOC124902310 (HGNC:):

LOC124902310 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.23359358).

BP6

Variant 9-136515323-C-T is Benign according to our data. Variant chr9-136515323-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264541.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, not_provided=1}.

BS2

High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.1981G>A	p.Gly661Ser	missense_variant	12/34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 linkuse as main transcript	c.1258G>A	p.Gly420Ser	missense_variant	9/31		XP_011517019.2
LOC124902310	XR_007061865.1 linkuse as main transcript	n.507+5344C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.1981G>A	p.Gly661Ser	missense_variant	12/34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000378

AC:

AN:

248364

Hom.:

AF XY:

0.000385

AC XY:

AN XY:

135234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000493

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:

0.000650

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000576

AC:

841

AN:

1460668

Hom.:

Cov.:

AF XY:

0.000561

AC XY:

408

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000696

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000341

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000532

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000587

AC:

ExAC

AF:

0.000380

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2024	Published functional studies suggest that this variant is associated with reduced ligand-induced Notch1 signaling, possibly due to reduced cell surface expression; however, a specific mechanism was not established and it is not known whether the experimental conditions represent the physiologic effect of the variant in vivo (PMID: 20951801, 18593716); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 26164125, 21563298, 18593716, 32165302, 36599283, 30582441, 20951801, 29641532) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 06, 2022	BS1, PP2, PS4_moderate -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The p.G661S variant (also known as c.1981G>A), located in coding exon 12 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 1981. The glycine at codon 661 is replaced by serine, an amino acid with similar properties. Among patients in a cohort with left ventricular outflow tract malformations, this variant was reported in four patients who exhibited bicuspid aortic valve, aortic valve stenosis, coarctation of the aorta, or hypoplastic left heart syndrome, and in all four cases, this variant also was described in an unaffected parent (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93). In the same study, this variant was reported in 1/212 healthy control subjects. Further in vitro functional analysis of this variant demonstrated only slight or no difference compared to wild-type, in surface protein, ligand-activated signaling, trafficking or folding (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93; Riley MF et al. Biochim Biophys Acta. 2011;1812(1):121-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Pulmonary arterial hypertension

Benign:1

Likely benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

Aortic valve disease 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Adams-Oliver syndrome 5 (MIM#616028) and aortic valve disease 1 (MIM#109730). A gain of function mechanism has also been described, but this is more in association with cancer (OMIM, PMID: 30582441). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30582441). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (101 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS, and has been observed in at least four individuals with congenital cardiovascular malformations but also within a control cohort (ClinVar, PMID: 18593716). (I) 1010 - Functional evidence for this variant is inconclusive. Transfected NIH3T3 cells demonstrated similar luciferase activity and protein expression to wildtype cells, but a significant decrease in ligand induction. It is unclear if this reduction is enough to induce disease in an in vivo setting (PMID: 18593716). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Adams-Oliver syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Aortic valve disorder;C3280182:Adams-Oliver syndrome 2

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 10-28-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.37

Eigen

Benign

-0.0095

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.037

MutationAssessor

Benign

0.24

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.45

Sift

Benign

0.74

Sift4G

Benign

0.80

Polyphen

0.91

Vest4

0.56

MVP

0.78

MPC

0.97

ClinPred

0.10

GERP RS

4.8

Varity_R

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over