Submissions for variant NM_014141.6(CNTNAP2):c.1385G>A (p.Arg462His)

gnomAD frequency: 0.00004  dbSNP: rs774717843

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187184	SCV000240764	uncertain significance	not provided	2012-11-05	criteria provided, single submitter	clinical testing	p.Arg462His (CGC>CAC):c.1385 G>A in exon 9 of the CNTNAP2 gene (NM_014141.4). The Arg462His 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 Arg426His in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Arg462His alters a highly conserved position in the second laminin G-like domain of the protein. However, missense mutations have not been reported in this region of the protein. Additionally, this amino acid substitution is conservative, as Arginine and Histidine are both positively charged amino acids. Multiple in silico algorithms predict Arg462His may be benign. Therefore, based on the currently available information, it is unclear whether Arg462His is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470762	SCV000553439	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-08-31	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 462 of the CNTNAP2 protein (p.Arg462His). This variant is present in population databases (rs774717843, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 205243). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV002390490	SCV002699031	uncertain significance	Inborn genetic diseases	2019-06-03	criteria provided, single submitter	clinical testing	The p.R462H variant (also known as c.1385G>A), located in coding exon 9 of the CNTNAP2 gene, results from a G to A substitution at nucleotide position 1385. The arginine at codon 462 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV000470762	SCV001423405	not provided	Cortical dysplasia-focal epilepsy syndrome		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 01-18-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.