Submissions for variant NM_017617.5(NOTCH1):c.6205G>A (p.Ala2069Thr)

gnomAD frequency: 0.00001  dbSNP: rs567909904

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208466	SCV000264134	uncertain significance	Marfan syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060006	SCV001224665	likely benign	Adams-Oliver syndrome 5	2024-08-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001509385	SCV001716062	uncertain significance	not provided	2020-07-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001509385	SCV001764889	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001060006	SCV002553313	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270023	SCV002553315	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002363043	SCV002656970	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-07-28	criteria provided, single submitter	clinical testing	The p.A2069T variant (also known as c.6205G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 6205. The alanine at codon 2069 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002500668	SCV002806915	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2022-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401116	SCV004122768	likely benign	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.6205G>A (p.Ala2069Thr) results in a non-conservative amino acid change in 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 5e-05 in 238404 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 464-fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.6205G>A has been reported in the literature in at least one individual with an unspecified rare disease who also carried another NOTCH1 variant (e.g. Stranneheim_2021). These report(s) do 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 has been ascertained in the context of this evaluation (PMID: 33726816). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.