ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.3032C>T (p.Thr1011Met) (rs199980022)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188286 SCV000241897 uncertain significance not provided 2012-12-28 criteria provided, single submitter clinical testing p.Thr1051Met (ACG>ATG): c.3152 C>T in exon 16 of the NRXN1 gene (NM_001135659.1) The Thr1051Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Thr1051Met in approximately 6,300 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a polar Threonine residue is replaced by a non-polar Methionine residue. It alters a highly conserved position in the fifth laminin G-like domain. However, missense mutations have not been previously reported in this region of the protein, and multiple in silico algorithms predict Thr1051Met is likely benign. Therefore, based on the currently available information, it is unclear whether Thr1051Met is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000552360 SCV000651821 uncertain significance Pitt-Hopkins-like syndrome 2 2019-07-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1051 of the NRXN1 protein (p.Thr1051Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199980022, ExAC 0.009%) but has not been reported in the literature in individuals with an NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206255). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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