Submissions for variant NM_001330078.2(NRXN1):c.407A>G (p.Lys136Arg)

gnomAD frequency: 0.00001  dbSNP: rs202118977

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188311	SCV000241922	uncertain significance	not provided	2018-07-24	criteria provided, single submitter	clinical testing	The c.407 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.407 A>G variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In-silico splice prediction models predict c.407 A>G may create a cryptic donor site. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.407 A>G does not alter splicing, it will result in the K136R missense change. This substitution occurs at an amino acid position that is conserved in mammals; however, Arginine is observed at this position in evolution. The K136R 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 predicts this variant likely does not alter 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223877	SCV001396045	uncertain significance	Pitt-Hopkins-like syndrome 2	2023-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 136 of the NRXN1 protein (p.Lys136Arg). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 206277). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. This variant is present in population databases (rs202118977, gnomAD 0.0009%).