Submissions for variant NM_000435.3(NOTCH3):c.986G>A (p.Cys329Tyr)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001288901	SCV001476307	pathogenic	not provided	2020-04-17	criteria provided, single submitter	clinical testing	The variant disrupts a cysteine residue in an EGF-like repeat domain, which is important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.
PreventionGenetics, part of Exact Sciences	RCV004727078	SCV005339794	likely pathogenic	NOTCH3-related disorder	2024-06-04	no assertion criteria provided	clinical testing	The NOTCH3 c.986G>A variant is predicted to result in the amino acid substitution p.Cys329Tyr. This variant was reported in at least one individual with CADASIL (Mukai et al. 2020. PubMed ID: 32277177). This variant has not been reported in a large population database, indicating this variant is rare. Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant alters a cysteine residue and is located in the extracellular EGF-like domain eight. Pathogenic variants in EGF-like domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGF-like domains 7-34 have a much higher population frequency, and can predispose to a milder small-vessel disease, possibly even displaying incomplete or at least very late onset complete penetrance (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as likely pathogenic.

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