rs1064796983

Positions:

• chr9-136502021-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_017617.5(NOTCH1):​c.5452C>G​(p.Leu1818Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.838

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.24874341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.5452C>G	p.Leu1818Val	missense_variant	29/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.4729C>G	p.Leu1577Val	missense_variant	26/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5452C>G	p.Leu1818Val	missense_variant	29/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460954 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726794

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 AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adams-Oliver syndrome 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Dec 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

NOTCH1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2023

The NOTCH1 c.5452C>G variant is predicted to result in the amino acid substitution p.Leu1818Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2016

The p.L1818V variant (also known as c.5452C>G), located in coding exon 29 of the NOTCH1 gene, results from a C to G substitution at nucleotide position 5452. The leucine at codon 1818 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6053 samples (12106 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2017

The L1818V variant has not been published as pathogenic or been reported as benign to our knowledge. The L1818V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. Nevertheless, the L1818V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Aortic valve disease 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.17
Sift	Benign	0.73	T
Sift4G	Benign	0.51	T
Polyphen		0.74	P
Vest4		0.34
MutPred		0.26		Gain of loop (P = 0.069);
MVP		0.86
MPC		0.95
ClinPred		0.28	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034

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: rs1064796983; hg19: chr9-139396473;