ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.3179C>T (p.Ala1060Val) (rs369254596)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766801 SCV000240809 uncertain significance not provided 2018-04-06 criteria provided, single submitter clinical testing The A1060V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. It is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The A1060V substitution occurs at a position that is conserved in mammals but not in more distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the A1060V variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Athena Diagnostics Inc RCV000187227 SCV000612859 uncertain significance not specified 2017-03-29 criteria provided, single submitter clinical testing
Invitae RCV000702358 SCV000831210 uncertain significance Pitt-Hopkins-like syndrome 1 2018-05-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1060 of the CNTNAP2 protein (p.Ala1060Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs369254596, ExAC 0.009%). This variant has been observed in an individual with persistent developmental stuttering (PMID: 24807205). ClinVar contains an entry for this variant (Variation ID: 205282). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000719303 SCV000850169 uncertain significance History of neurodevelopmental disorder 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000765938 SCV000897358 uncertain significance Autism 15; Pitt-Hopkins-like syndrome 1 2018-10-31 criteria provided, single submitter clinical testing

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