Submissions for variant NM_017617.5(NOTCH1):c.335G>A (p.Arg112His)

dbSNP: rs768625801

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522642	SCV000618110	uncertain significance	not provided	2017-09-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NOTCH1 gene. The R112H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, R112H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and histidine (H) is the wild-type residue at this position in at least one non-mammalian species. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199078	SCV001370073	uncertain significance	Aortic valve disease 1	2019-05-07	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851497	SCV002207964	uncertain significance	Adams-Oliver syndrome 5	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the NOTCH1 protein (p.Arg112His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449741). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH1 protein function. 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.
Genome-Nilou Lab	RCV001851497	SCV002554016	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001199078	SCV002554017	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323887	SCV002606774	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-08-23	criteria provided, single submitter	clinical testing	The p.R112H variant (also known as c.335G>A), located in coding exon 3 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 335. The arginine at codon 112 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available 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.