ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5572A>C (p.Met1858Leu)

gnomAD frequency: 0.00001  dbSNP: rs779337715
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002315138 SCV000739510 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-01-22 criteria provided, single submitter clinical testing The c.5572A>C (p.M1858L) alteration is located in exon 30 (coding exon 30) of the NOTCH1 gene. This alteration results from a A to C substitution at nucleotide position 5572, causing the methionine (M) at amino acid position 1858 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000698240 SCV000826894 benign Adams-Oliver syndrome 5 2023-10-23 criteria provided, single submitter clinical testing
GeneDx RCV001788302 SCV002030841 uncertain significance not provided 2021-11-23 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; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 520094; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Genome-Nilou Lab RCV000698240 SCV002553333 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270920 SCV002553334 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586834 SCV005077491 likely benign not specified 2024-04-29 criteria provided, single submitter clinical testing Variant summary: NOTCH1 c.5572A>C (p.Met1858Leu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 247270 control chromosomes. The observed variant frequency is approximately 71 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 benign. To our knowledge, no occurrence of c.5572A>C 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: 520094). Based on the evidence outlined above, the variant was classified as likely benign.

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