rs201620358

Variant names:

• chr9-136510659-G-A
• rs201620358
• NM_017617.5:c.2734C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136510659-G-A
• chr9-136510659-G-C
• chr9-136510659-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.2734C>T​(p.Arg912Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,605,840 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:13 O:1
• Conservation: PhyloP100: 2.57

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]

LOC124902310 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105588555).
• BP6: Variant 9-136510659-G-A is Benign according to our data. Variant chr9-136510659-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134921.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=5, not_provided=1}. Variant chr9-136510659-G-A is described in Lovd as [Likely_benign]. Variant chr9-136510659-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00219 (333/152362) while in subpopulation NFE AF= 0.00345 (235/68028). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 333 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.2734C>T	p.Arg912Trp	missense_variant	Exon 17 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.2011C>T	p.Arg671Trp	missense_variant	Exon 14 of 31		XP_011517019.2
LOC124902310	XR_007061864.1	n.508-371G>A		intron_variant	Intron 1 of 1
LOC124902310	XR_007061865.1	n.507+680G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.2734C>T	p.Arg912Trp	missense_variant	Exon 17 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00170 AC: 394 AN: 231904 Hom.: 1 AF XY: 0.00161 AC XY: 205 AN XY: 127698

Gnomad AFR exome AF: 0.000562

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.000513

Gnomad EAS exome AF: 0.000172

Gnomad SAS exome AF: 0.0000997

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00265 AC: 3857 AN: 1453478 Hom.: 8 Cov.: 32 AF XY: 0.00251 AC XY: 1816 AN XY: 723180

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00189

Gnomad4 ASJ exome AF: 0.000691

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00233

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152362 Hom.: 0 Cov.: 34 AF XY: 0.00204 AC XY: 152 AN XY: 74502

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00345

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00293 Hom.: 1

Bravo AF: 0.00215

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000495 AC: 2

ESP6500EA AF: 0.00324 AC: 27

ExAC AF: 0.00163 AC: 196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH1: PP2, BS1, BS2 -

Jul 29, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 04, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOTCH1 c.2734C>T; p.Arg912Trp variant (rs201620358) is reported in the literature in individuals with aortic valve stenosis, aortic root aneurysm, bicuspid aortic valve, or coarctation of the aorta (Kerstjens-Frederikse 2016, Ziganshin 2015). Incomplete penetrance and variable expressivity are reported for NOTCH1 (Roifman 2021). This variant is also reported in ClinVar (Variation ID: 134921). This variant is found in the general population with an overall allele frequency of 0.18% (469/263284 alleles, including one homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.402). Based on the available information, the clinical significance of this variant is uncertain. References: Kerstjens-Frederikse WS et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016 Sep;18(9):914-23. PMID: 26820064. Roifman M et al. Heterozygous NOTCH1 deletion associated with variable congenital heart defects. Clin Genet. 2021 Jun;99(6):836-841. PMID: 33630301. Ziganshin BA et al. Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting. Ann Thorac Surg. 2015 Nov;100(5):1604-11. PMID: 26188975. -

not specified Uncertain:1 Benign:2 Other:1

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Apr 21, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R912W variant of uncertain significance in the NOTCH1 gene has previously been reported in a 52 year-old male with an aortic root aneurysm and bicuspid aortic valve (Ziganshin et al., 2015). This variant has also been reported in 5 unrelated Dutch individuals with left-sided congenital heart defects; one individual with a bicuspid aortic valve, one individual with aortic valve stenosis, and three individuals with coarctation of the aorta (Kerstjens-Frederikse et al., 2016). For one of the individuals with coarctation of the aorta, this variant was also found in the father who had a bicuspid aortic valve; segregation studies for the remaining four individuals were either not completed or non-informative (Kerstjens-Frederikse et al., 2016). R912W was observed in approximately 0.3% of alleles from individuals of European (Non-Finnish) ancestry and 0.2% of alleles from individuals of both Latino and European (Finnish) ancestry in the Exome Aggregation Consortium, indicating it may be a rare benign variant in these populations (Lek et al., 2016). Furthermore, this substitution occurs at a position that is not conserved across species. Nevertheless, R912W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Jan 29, 2014

Blueprint Genetics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH1 NM_017617.5 exon 17 p.Arg912Trp (c.2734C>T): This variant has been reported in the literature in one individual with an aortic aneurysm and in five individuals with nonsyndromic congenital heart disease (bicuspid aortic valve, coarctation of the aorta, aortic valve stenosis) (Ziganshin 2015 PMID:26188975, Kerstijens-Frederikse 2016 PMID:26820064). However, this variant is also present in 0.2% (317/119414) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/9-139405111-G-A). This variant is present in ClinVar (Variation ID:134921). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aortic valve disease 1 Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Adams-Oliver syndrome 5 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Connective tissue disorder Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.96	L
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.74
MPC		1.0
ClinPred		0.032	T
GERP RS		2.9
Varity_R		0.14

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: rs201620358; hg19: chr9-139405111; COSMIC: COSV53040452;