Submissions for variant NM_001378964.1(CDON):c.791C>A (p.Pro264Gln)

gnomAD frequency: 0.00012  dbSNP: rs140542787

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481702	SCV000571851	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing	The P264Q variant in the CDON gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P264Q variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The P264Q variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret P264Q as a variant of uncertain significance
Illumina Laboratory Services, Illumina	RCV001103943	SCV001260765	likely benign	Holoprosencephaly 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV002525909	SCV003676802	likely benign	Inborn genetic diseases	2022-10-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001103943	SCV004371474	uncertain significance	Holoprosencephaly 11	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 264 of the CDON protein (p.Pro264Gln). This variant is present in population databases (rs140542787, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CDON-related conditions. ClinVar contains an entry for this variant (Variation ID: 422386). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDON protein function with a negative predictive value of 80%. 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.