ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.2110G>A (p.Gly704Arg) (rs757547387)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188258 SCV000241868 uncertain significance not provided 2017-10-03 criteria provided, single submitter clinical testing The G744R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G744R variant is observed in 14/18866 (0.1%) alleles from individuals of East Asian background (Lek et al., 2016). The G744R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000819138 SCV000959781 uncertain significance Pitt-Hopkins-like syndrome 2 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 744 of the NRXN1 protein (p.Gly744Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs757547387, ExAC 0.07%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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