ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.1784G>A (p.Arg595His)

gnomAD frequency: 0.00001  dbSNP: rs761279630
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479818 SCV000573170 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NRXN1 gene. The R635H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R635H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the R635H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Fulgent Genetics, Fulgent Genetics RCV000764445 SCV000895502 uncertain significance Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003114611 SCV003786375 uncertain significance Pitt-Hopkins-like syndrome 2 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 635 of the NRXN1 protein (p.Arg635His). This variant is present in population databases (rs761279630, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423467). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics RCV004955535 SCV005461954 uncertain significance Inborn genetic diseases 2024-10-07 criteria provided, single submitter clinical testing The c.1904G>A (p.R635H) alteration is located in exon 11 (coding exon 10) of the NRXN1 gene. This alteration results from a G to A substitution at nucleotide position 1904, causing the arginine (R) at amino acid position 635 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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