ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.1879G>A (p.Val627Ile) (rs147447659)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716675 SCV000847517 uncertain significance History of neurodevelopmental disorder 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000187194 SCV000240774 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing p.Val627Ile (GTT>ATT): c.1879 G>A in exon 12 of the CNTNAP2 gene (NM_014141.5). The V627I variant has been reported previously in an individual with persistent developmental stuttering; however, additional information regarding the phenotype of the individual and information about parental testing were not provided and the authors concluded that CNTNAP2 variants were not associated with stuttering (Han et al., 2014). The V627I variant is observed in 11/24034 (0.05%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016). The V627I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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. The variant is found in EPILEPSY,INFANT-EPI panel(s).
Invitae RCV000644710 SCV000766413 uncertain significance Pitt-Hopkins-like syndrome 1 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 627 of the CNTNAP2 protein (p.Val627Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs147447659, ExAC 0.05%). This variant has been reported in the literature in an individual with specific language impairment (PMID: 24807205). ClinVar contains an entry for this variant (Variation ID: 205251). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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