ClinVar Genomic variation as it relates to human health

Variant summary: CTNS c.18_21delGACT (p.Thr7PhefsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.646dupA/p.Thr216fsX12). The variant allele was found at a frequency of 5.4e-05 in 277224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CTNS causing Cystinosis (5.4e-05 vs 0.0025). c.18_21delGACT has been reported in the literature in multiple individuals affected with Cystinosis. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000188834, PMID:9537412). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000594). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The frameshift deletion p.T7Ffs*7 in CTNS (NM_004937.3) has been observed as homozygous or in combination with another CTNS variant in individuals and families affected with nephropathic cystinosis (Town M et al; Onenli et al). The variant has been reported to ClinVar as Pathogenic. The p.T7Ffs*7 variant is observed in 4/30,612 (0.0131%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The p.T7Ffs*7 variant is a loss of function variant in the gene CTNS, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_004928.2:p.T7Ffs*7 and 26 others. For these reasons, this variant has been classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Thr7Phefs*7) in the CTNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNS are known to be pathogenic (PMID: 9537412, 27102039). This variant is present in population databases (rs764835663, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with nephropathic cystinosis (PMID: 9537412, 28276207). ClinVar contains an entry for this variant (Variation ID: 188834). For these reasons, this variant has been classified as Pathogenic.

The CTNS c.18_21delGACT variant is predicted to result in a frameshift and premature protein termination (p.Thr7Phefs*7). This variant, also referred to as 357delGACT, has been reported in the homozygous and compound heterozygous state in cystinosis patients (e.g., Town et al. 1998. PubMed ID: 9537412; Macías-Vidal et al. 2009. PubMed ID: 19863563; Ghazi et al. 2017. PubMed ID: 28238446). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org). Frameshift variants in CTNS are expected to be pathogenic. This variant is interpreted as pathogenic.