Submissions for variant NM_017617.5(NOTCH1):c.3853G>A (p.Val1285Met)

gnomAD frequency: 0.00007  dbSNP: rs756972680

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519706	SCV000618910	uncertain significance	not provided	2020-11-16	criteria provided, single submitter	clinical testing	Reported in one proband with hypoplastic left heart syndrome, though clinical and segregation details are not available (Helle et al., 2019); Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 450338; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25587027, 30511478)
Invitae	RCV000693083	SCV000820938	benign	Adams-Oliver syndrome 5	2023-12-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000693083	SCV002553467	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270629	SCV002553468	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002367734	SCV002623685	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-27	criteria provided, single submitter	clinical testing	The p.V1285M variant (also known as c.3853G>A), located in coding exon 23 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 3853. The valine at codon 1285 is replaced by methionine, an amino acid with highly similar properties. This variant was detected in one individual with hypoplastic left heart syndrome (Helle E et al. Genet. Epidemiol., 2019 03;43:215-226). This alteration has also been reported in an ischemic stroke cohort (Alkhamis FA et al. Funct Integr Genomics, 2023 Mar;23:102). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV003224309	SCV003920299	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2021-03-30	criteria provided, single submitter	clinical testing	NOTCH1 NM_017617.5 exon 23 p.Val1285Met (c.3853G>A): This variant has not been reported in the literature but is present in 0.007% (9/121848) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/9-139401216-C-T). This variant is present in ClinVar (Variation ID:450338). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330741	SCV004039480	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.3853G>A (p.Val1285Met) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 236138 control chromosomes (gnomAD). The observed variant frequency is approximately 88 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 (6.3e-07), strongly suggesting that the variant is benign. c.3853G>A has been reported in the literature in one individual affected with Hypolastic Left Heart Syndrome without evidence of segregation (Helle_2019). This report does not provide unequivocal conclusions about association of the variant with Adams-Oliver Syndrome 5. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30511478). Five ClinVar submitters have assessed this variant since 2014: four classified the variant as uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291516	SCV001480024	uncertain significance	Hypoplastic left heart syndrome		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000519706	SCV001549993	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NOTCH1 p.Val1285Met variant was identified in 1/49 probands with hypoplastic left heart syndrome (Helle_2017_PMID:30511478) and 1/108 B-chronic lymphocytic leukemia patients (Athanasakis_2014_PMID:25587027). The variant was identified in dbSNP (ID: rs756972680), ClinVar (classified as uncertain significance by GeneDx and Invitae for Adams-Oliver Syndrome 5) and LOVD 3.0 (classified as uncertain significance by VKGL-NL). The variant was identified in control databases in 14 of 267496 chromosomes at a frequency of 0.00005234 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 3 of 6838 chromosomes (freq: 0.000439), European (non-Finnish) in 9 of 121848 chromosomes (freq: 0.000074), South Asian in 1 of 29434 chromosomes (freq: 0.000034) and Latino in 1 of 34386 chromosomes (freq: 0.000029), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val1285 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000519706	SCV001929963	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000519706	SCV001953549	uncertain significance	not provided		no assertion criteria provided	clinical testing