ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6685G>A (p.Val2229Met) (rs202096917)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243310 SCV000320621 uncertain significance Cardiovascular phenotype 2018-09-25 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
Invitae RCV000467175 SCV000548950 uncertain significance Adams-Oliver syndrome 5 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 2229 of the NOTCH1 protein (p.Val2229Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs202096917, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family affected with Tetralogy of Fallot (PMID: PMID:25931334). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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