Submissions for variant NM_017617.5(NOTCH1):c.2108G>A (p.Arg703His)

gnomAD frequency: 0.00004  dbSNP: rs561126575

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000544874	SCV000659391	likely benign	Adams-Oliver syndrome 5	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313933	SCV000739354	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-02-16	criteria provided, single submitter	clinical testing	The p.R703H variant (also known as c.2108G>A), located in coding exon 13 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 2108. The arginine at codon 703 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001358460	SCV001986432	uncertain significance	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
PreventionGenetics, part of Exact Sciences	RCV003945094	SCV004770487	uncertain significance	NOTCH1-related condition	2024-02-02	criteria provided, single submitter	clinical testing	The NOTCH1 c.2108G>A variant is predicted to result in the amino acid substitution p.Arg703His. To our knowledge, this variant has not been reported to be associated with disease in the literature. This variant is reported in 0.047% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI	RCV000121662	SCV000085860	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358460	SCV001554201	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NOTCH1 p.Arg703His variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs561126575), ClinVar (classified as uncertain significance by Ambry Genetics and Invitae; associated conditions are Adams-Oliver syndrome 5 and cardiovascular phenotype), and in Cosmic (FATHMM prediction of Pathogenic; score 0.75). The variant was also identified in control databases in 28 of 238950 chromosomes at a frequency of 0.000117 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 14 of 29858 chromosomes (freq: 0.000469), Other in 5 of 5754 chromosomes (freq: 0.000869), Latino in 1 of 33802 chromosomes (freq: 0.00003), European (non-Finnish) in 7 of 108000 chromosomes (freq: 0.000065), and African in 1 of 14228 chromosomes (freq: 0.00007), while the variant was not observed in the European (Finnish), East Asian, and Ashkenazi Jewish populations. 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 at the variant location. The p.Arg703 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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.