ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.3010G>A (p.Asp1004Asn) (rs748508785)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520214 SCV000621123 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing The D1004N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D1004N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D1004N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000552031 SCV000645099 uncertain significance Pitt-Hopkins-like syndrome 1 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1004 of the CNTNAP2 protein (p.Asp1004Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 18 of the CNTNAP2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs748508785, ExAC 0.02%) but has not been reported in the literature in individuals with a CNTNAP2-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare silent change with uncertain impact on mRNA splicing. It has been classified as a Variant of Uncertain Significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767939 SCV000898624 uncertain significance Autism 15; Pitt-Hopkins-like syndrome 1 2018-07-31 criteria provided, single submitter clinical testing CNTNAP2 NM_014141.5 exon 18 p.Asp1004Asn (c.3010G>A):This variant has not been reported in the literature but is present in 2/17248 East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs748508785). This variant is present in ClinVar (Variation ID:452326). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant occurs in the last nucleotide of the exon; however, computational prediction tools do not suggest that it may alter splicing. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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