Submissions for variant NM_001159773.2(CANT1):c.896C>T (p.Pro299Leu)

gnomAD frequency: 0.00001  dbSNP: rs267606700

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003398396	SCV004106085	likely pathogenic	CANT1-related disorder	2023-10-09	criteria provided, single submitter	clinical testing	The CANT1 c.896C>T variant is predicted to result in the amino acid substitution p.Pro299Leu. This variant along with a second variant in this gene was reported in two children in one in family with Desbuquois dysplasia (Huber et al. 2009. PubMed ID: 19853239) and found in the homozygous condition in another individual with Desbuquois dysplasia (Biji et al. 2023. PubMed ID: 36331722). This variant is reported in 0.0057% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-76989942-G-A). This variant is interpreted as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000307	SCV006070924	likely pathogenic	Desbuquois dysplasia 1	2025-03-27	criteria provided, single submitter	clinical testing	Variant summary: CANT1 c.896C>T (p.Pro299Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229040 control chromosomes. c.896C>T has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with Desbuquois dysplasia 1 (Biji_2023, Huber_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36331722, 19853239). ClinVar contains an entry for this variant (Variation ID: 283). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000000307	SCV000020451	pathogenic	Desbuquois dysplasia 1	2009-11-01	no assertion criteria provided	literature only
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000000307	SCV002072474	pathogenic	Desbuquois dysplasia 1	2022-01-30	no assertion criteria provided	clinical testing	The homozygous mis-sense variant c.896C>T (p.P299L) has been previously reported by Huber C et al in 2009 as a heterozygous variant in a Brazilian patient. The allele frequency is 0.0004% in gnomAD (aggregated) database. In-silico bioinformatic software predict this variant by mutation taster as Disease causing and SIFT & PROVEAN as Damaging. The phenotype observed was mesomelic shortening of limbs, cystic hygroma, hypoplastic pulmonary artery, hypoplastic lungs, cleft palate, renal cysts, non-immune fetal hydrops. Desbuquois Dysplasia 1 is an autosomal recessive disorder. Based on the phenotypic observation, we classify this variant as likely pathogenic.