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

gnomAD frequency: 0.00006  dbSNP: rs561126575

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544874	SCV000659391	likely benign	Adams-Oliver syndrome 5	2024-09-17	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 c.2108G>A (p.R703H) alteration is located in exon 13 (coding exon 13) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 2108, causing the arginine (R) at amino acid position 703 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001358460	SCV001986432	uncertain significance	not provided	2025-03-31	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121662	SCV005185178	likely benign	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.2108G>A (p.Arg703His) results in a non-conservative amino acid change located in the EGF like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 238950 control chromosomes. The observed variant frequency is approximately 190 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.2108G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134912). Based on the evidence outlined above, the variant was classified as likely benign.
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.
PreventionGenetics, part of Exact Sciences	RCV004542903	SCV004770487	uncertain significance	NOTCH1-related disorder	2024-02-02	no assertion criteria provided	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.