Submissions for variant NM_001159773.2(CANT1):c.734C>T (p.Pro245Leu)

gnomAD frequency: 0.00001  dbSNP: rs761853610

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002250651	SCV002521259	pathogenic	Desbuquois dysplasia 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32907608). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.17). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CANT1- related disorder (PMID: 32907608). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520404	SCV004266670	likely pathogenic	not provided	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 245 of the CANT1 protein (p.Pro245Leu). This variant is present in population databases (rs761853610, gnomAD 0.003%). This missense change has been observed in individual(s) with desbuquois dysplasia (PMID: 32907608). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 452497). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CANT1 protein function. Experimental studies have shown that this missense change affects CANT1 function (PMID: 32907608). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000520404	SCV000621309	uncertain significance	not provided	2017-10-03	flagged submission	clinical testing	The P245L variant in the CANT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P245L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P245L as a variant of uncertain significance.