Submissions for variant NM_014141.6(CNTNAP2):c.3385G>C (p.Asp1129His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003085603	SCV003462036	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-04-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1129 of the CNTNAP2 protein (p.Asp1129His). This variant is present in population databases (rs781236853, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of CNTNAP2-related conditions (PMID: 26350204). 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 disruptive. Experimental studies have shown that this missense change affects CNTNAP2 function (PMID: 22872700, 29788201). 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.
GeneDx	RCV003332405	SCV004040139	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect, as variant causes protein misfolding, resulting in ER sequestration and reduction of axon growth in cortical neurons (PMID: 22872700, 29788201); Observed in individuals with intellectual disability and/or autism in published literature (PMID: 26350204, 18179895); This variant is associated with the following publications: (PMID: 29788201, 18179895, 22872700, 26350204)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239639	SCV005884484	uncertain significance	not specified	2024-12-24	criteria provided, single submitter	clinical testing	Variant summary: CNTNAP2 c.3385G>C (p.Asp1129His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251456 control chromosomes (gnomAD). c.3385G>C has been reported in the literature in individuals affected with Autism or Intellectual disability without strong evidence of causality (Bakkaloglu_2008, Grozeva_2015). These reports do not provide unequivocal conclusions about association of the variant with Autism, Susceptibility To, 15. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced mature/immature protein ratios, causes trafficking deficits and is retained in the endoplasmic reticulum (Falivelli_2012, Canali_2018, Zhang_2024). ClinVar contains an entry for this variant (Variation ID: 2153316). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.