Submissions for variant NM_017617.5(NOTCH1):c.7313C>T (p.Pro2438Leu)

gnomAD frequency: 0.00008  dbSNP: rs199777870

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002315135	SCV000739504	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-07-31	criteria provided, single submitter	clinical testing	The p.P2438L variant (also known as c.7313C>T), located in coding exon 34 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 7313. The proline at codon 2438 is replaced by leucine, an amino acid with similar properties. This amino acid position is poorly 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768032	SCV000898859	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2021-03-30	criteria provided, single submitter	clinical testing	NOTCH1 NM_017617.4 exon 34 p.Pro2438Leu (c.7313C>T): This variant has not been reported in the literature but is present in 2/34172 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs199777870). This variant is present in ClinVar (Variation ID:520091). This variant amino acid Leucine (Leu) is present in >40 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV001584443	SCV001819012	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Has not been previously published in association with cardiac disorders as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32941702, 36931573)
Invitae	RCV001855283	SCV002284582	benign	Adams-Oliver syndrome 5	2022-10-24	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001855283	SCV002555202	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270918	SCV002555203	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002315135	SCV003837911	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-24	criteria provided, single submitter	clinical testing