Submissions for variant NM_000435.3(NOTCH3):c.4914A>G (p.Glu1638=)

gnomAD frequency: 0.00003  dbSNP: rs149222385

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001125635	SCV001284728	uncertain significance	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, 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.
Athena Diagnostics	RCV001288089	SCV001474937	uncertain significance	not provided	2019-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288089	SCV002205597	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	This sequence change affects codon 1638 of the NOTCH3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NOTCH3 protein. This variant is present in population databases (rs149222385, gnomAD 0.004%). This variant has been observed in individual(s) with clinical features of CADASIL (PMID: 24086431, 27881154). This variant is also known as Glu1638Glu. ClinVar contains an entry for this variant (Variation ID: 890786). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482246	SCV002788817	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1; Lateral meningocele syndrome; Myofibromatosis, infantile, 2	2021-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994218	SCV004813587	uncertain significance	not specified	2024-02-01	criteria provided, single submitter	clinical testing	Variant summary: NOTCH3 c.4914A>G alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.5e-05 in 239936 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4914A>G has been reported in the literature in several individuals with suspicious Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, and a familial/personal history of Ischemic Stroke (example, Maksemous_2016, Ross_2013). These report(s) do not provide unequivocal conclusions about association of the variant with NOTCH3-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27881154, 24086431). ClinVar contains an entry for this variant (Variation ID: 890786). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004538350	SCV004726067	likely benign	NOTCH3-related disorder	2021-09-17	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).