Submissions for variant NM_000435.3(NOTCH3):c.6239G>A (p.Arg2080Gln)

gnomAD frequency: 0.00009  dbSNP: rs759896413

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000625620	SCV001283505	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV003411477	SCV004140289	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003411477	SCV004526174	likely benign	not provided	2023-06-26	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000625620	SCV000746121	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2017-09-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737899	SCV005353548	uncertain significance	NOTCH3-related disorder	2024-07-11	no assertion criteria provided	clinical testing	The NOTCH3 c.6239G>A variant is predicted to result in the amino acid substitution p.Arg2080Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.