Submissions for variant NM_017617.5(NOTCH1):c.3510+3G>A

gnomAD frequency: 0.00003  dbSNP: rs372739350

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000527368	SCV000659424	uncertain significance	Adams-Oliver syndrome 5	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 21 of the NOTCH1 gene. It does not directly change the encoded amino acid sequence of the NOTCH1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 477915). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000659138	SCV000780953	uncertain significance	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764816	SCV000895967	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000659138	SCV001780479	likely benign	not provided	2020-10-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343924	SCV004074152	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-14	criteria provided, single submitter	clinical testing	The c.3510+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 21 in the NOTCH1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000659138	SCV004563217	likely benign	not provided	2023-09-15	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000659138	SCV001958112	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000659138	SCV001970789	likely benign	not provided		no assertion criteria provided	clinical testing