ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6376G>A (p.Gly2126Arg)

gnomAD frequency: 0.00014  dbSNP: rs572960572
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000229962 SCV000290297 likely benign Adams-Oliver syndrome 5 2024-11-21 criteria provided, single submitter clinical testing
GeneDx RCV002225529 SCV002504336 uncertain significance not provided 2024-11-05 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 has a deleterious effect on protein structure/function
Ambry Genetics RCV002365212 SCV002657885 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-06-10 criteria provided, single submitter clinical testing The c.6376G>A (p.G2126R) alteration is located in exon 34 (coding exon 34) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 6376, causing the glycine (G) at amino acid position 2126 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004800354 SCV005422629 likely benign not specified 2024-10-21 criteria provided, single submitter clinical testing Variant summary: NOTCH1 c.6376G>A (p.Gly2126Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 239872 control chromosomes. The observed variant frequency is approximately 180.096 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.6376G>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: 241160). Based on the evidence outlined above, the variant was classified as likely benign.

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