Submissions for variant NM_017617.5(NOTCH1):c.4031C>T (p.Thr1344Met)

dbSNP: rs201215245

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523711	SCV000618225	likely benign	not provided	2021-08-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26820064)
Invitae	RCV001078778	SCV000659438	likely benign	Adams-Oliver syndrome 5	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000770630	SCV000739413	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-07-06	criteria provided, single submitter	clinical testing	The p.T1344M variant (also known as c.4031C>T), located in coding exon 25 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 4031. The threonine at codon 1344 is replaced by methionine, an amino acid with similar properties. This alteration was described in patients with left-sided congenital heart disease (Kerstjens-Frederikse WS et al. Genet. Med., 2016 09;18:914-23). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098).This amino acid position is highly 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 variant remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770630	SCV000902081	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987578	SCV004803473	likely benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.4031C>T (p.Thr1344Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 215554 control chromosomes. The observed variant frequency is approximately 14-fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is benign. c.4031C>T has been reported in the literature as a VUS in individuals affected with left-sided congenital heart disease (Kerstjens-Frederikse_2016) and thoracic aortic aneurysm (Salmasi_2022), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26820064, 35830949). ClinVar contains an entry for this variant (Variation ID: 449810). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000523711	SCV001797871	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000523711	SCV001966219	uncertain significance	not provided		no assertion criteria provided	clinical testing