Submissions for variant NM_004366.6(CLCN2):c.937G>A (p.Asp313Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003832818	SCV004629998	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 313 of the CLCN2 protein (p.Asp313Asn). This variant is present in population databases (rs757494232, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CLCN2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN2 protein function. 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.
Regional Center For Medical Genetics Timis, Louis Turcanu Emergency Hospital for Children Timisoara	RCV004588509	SCV005077952	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 11	2024-07-12	criteria provided, single submitter	research	This variant is reported in healthy population databases with low frequency (gnomAD v4.1.0 exomes, f = 0.000009914). In silico predictions of this missense variant support pathogenicity. SpliceAI predictions support a possible mild RNA splicing impact of this variant. Therefore, the variant was classified as uncertain with criteria for pathogenicity, according to ACMG 2015 guidelines.