Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000336591 | SCV000404384 | pathogenic | Retinitis pigmentosa | 2018-05-07 | criteria provided, single submitter | clinical testing | The CA4 c.40C>T (p.Arg14Trp) variant has been reported in at least 37 individuals from three large families with autosomal dominant retinitis pigmentosa. The variant was shown to segregate with disease in at least two of these families (Rebello et al. 2004; Yang et al. 2005). The p.Arg14Trp variant was absent from 36 unaffected family members and 1200 control chromosomes (Rebello et al. 2004; Yang et al. 2005), but is reported at a frequency of 0.00072 in the European (non-Finnish) population of the Exome Aggregation Consortium. Rebello et al. (2004) showed a reduction of CA4 secretion in transfected COS-7 cells carrying the p.Arg14Trp variant, but secretion was comparable to wildtype in a second study that used transfected HEK293 cells (Yang et al. 2005). However, Yang et al. (2005) showed that the p.Arg14Trp variant decreased binding of the CA4 protein to NBC1, thereby disrupting NBC1-mediated recovery of intracellular pH after acid-load. Based on the collective evidence, the p.Arg14Trp variant is classified as pathogenic for autosomal dominant retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV001247433 | SCV001420855 | uncertain significance | not provided | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the CA4 protein (p.Arg14Trp). This variant is present in population databases (rs104894559, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 15090652, 15563508). ClinVar contains an entry for this variant (Variation ID: 17607). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CA4 function (PMID: 15090652, 15295099, 15563508, 20626030). 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. |
| OMIM | RCV000019173 | SCV000039461 | uncertain significance | Retinitis pigmentosa 17 | 2005-01-15 | no assertion criteria provided | literature only | |
| Prevention |
RCV003914854 | SCV004728842 | pathogenic | CA4-related disorder | 2024-02-14 | no assertion criteria provided | clinical testing | The CA4 c.40C>T variant is predicted to result in the amino acid substitution p.Arg14Trp. This variant has been reported to be causative for autosomal dominant retinitis pigmentosa in three unrelated families (Rebello et al. 2004. PubMed ID: 15090652; Yang et al. 2005. PubMed ID: 15563508). In one family the variant segregated with disease in 13 affected individuals across three generations (Yang et al. 2005. PubMed ID: 15563508). This variant is reported in 0.081% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. |