Submissions for variant NM_017617.5(NOTCH1):c.7397C>T (p.Thr2466Met)

gnomAD frequency: 0.00007  dbSNP: rs369167555

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229341	SCV000290311	benign	Adams-Oliver syndrome 5	2023-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000493754	SCV000582292	uncertain significance	not provided	2021-05-03	criteria provided, single submitter	clinical testing	Reported in a Dutch individual with hypoplastic left heart syndrome, however, it was also found in this individual's father who had a normal echocardiogram (Kerstjens-Frederikse et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 241169; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26820064, 26096009)
Genome-Nilou Lab	RCV000229341	SCV002555195	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270065	SCV002555196	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379017	SCV002673515	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-02	criteria provided, single submitter	clinical testing	The p.T2466M variant (also known as c.7397C>T), located in coding exon 34 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 7397. The threonine at codon 2466 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in an individual with hypoplastic left heart syndrome (Kerstjens-Frederikse WS et al. Genet. Med., 2016 09;18:914-23). This amino acid position is 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.
PreventionGenetics, part of Exact Sciences	RCV003417833	SCV004112896	uncertain significance	NOTCH1-related condition	2023-03-24	criteria provided, single submitter	clinical testing	The NOTCH1 c.7397C>T variant is predicted to result in the amino acid substitution p.Thr2466Met. This variant, interpreted as likely benign, has been reported in patient with hypoplastic left heart syndrome and was found to be inherited from a father with a normal echocardiogram (Table S1 in Kerstjens-Frederikse et al. 2016. PubMed ID: 26820064). This variant is reported in 0.0081% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139390794-G-A). This variant has been interpreted as uncertain by multiple submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/241169/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000493754	SCV001550821	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NOTCH1 p.Thr2466Met variant was identified in the literature in a patient with hypoplastic left heart syndrome (Kerstjens-Frederikse_2016_PMID:26820064). The variant was identified in dbSNP (ID: rs369167555) and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 9 of 216528 chromosomes at a frequency of 0.00004157 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 8 of 98176 chromosomes (freq: 0.000081) and Latino in 1 of 30988 chromosomes (freq: 0.000032), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Thr2466 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000493754	SCV001927003	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000493754	SCV001953653	uncertain significance	not provided		no assertion criteria provided	clinical testing