Submissions for variant NM_000435.3(NOTCH3):c.6809C>T (p.Thr2270Met)

gnomAD frequency: 0.00011  dbSNP: rs148716935

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516212	SCV000614331	benign	not specified	2017-06-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000981773	SCV001129774	likely benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001123434	SCV001282275	likely benign	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetics and Molecular Pathology, SA Pathology	RCV002272275	SCV002556616	likely benign	Myofibromatosis, infantile, 2	2021-01-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000981773	SCV001549881	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NOTCH3 p.Thr2270Met variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs148716935) and ClinVar (classified as benign by Athena Diagnostics Inc). The variant was identified in control databases in 40 of 282300 chromosomes at a frequency of 0.0001417 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 24 of 10356 chromosomes (freq: 0.002317), African in 3 of 24838 chromosomes (freq: 0.000121), Latino in 3 of 35424 chromosomes (freq: 0.000085) and European (non-Finnish) in 10 of 128818 chromosomes (freq: 0.000078), but was not observed in the East Asian, European (Finnish), Other, or South Asian populations. The p.Thr2270 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.
PreventionGenetics, part of Exact Sciences	RCV004541611	SCV004763631	likely benign	NOTCH3-related disorder	2022-03-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).