Submissions for variant NM_014141.6(CNTNAP2):c.3155G>A (p.Arg1052His)

gnomAD frequency: 0.00009  dbSNP: rs374739970

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187225	SCV000240807	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Illumina Laboratory Services, Illumina	RCV000266198	SCV000467285	uncertain significance	Pitt-Hopkins-like syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000321341	SCV000467286	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000321341	SCV000645103	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-07-04	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 1052 of the CNTNAP2 protein (p.Arg1052His). This variant is present in population databases (rs374739970, gnomAD 0.01%). 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: 205280). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics	RCV000765937	SCV000897357	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321753	SCV002610147	likely benign	Inborn genetic diseases	2019-01-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000321341	SCV002769441	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene (OMIM). 0106 - This gene is known to be associated with autosomal recessive disease (OMIM). 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 19). 0304 - Variant is present in gnomAD <0.01 for recessive indication. 0309 - An alternative amino acid change at the same position has been observed in gnomAD. 0503 - Missense variant consistently predicted to be tolerated OR not conserved in mammals with a minor amino acid change. 0604 - Variant is not located in an established domain, motif or hotspot. 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant.