Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001852700 | SCV002274356 | likely pathogenic | Dilated cardiomyopathy 1II | 2023-12-20 | 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 56 of the CRYAB protein (p.Arg56Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive juvenile cataracts and/or unexplained limb-girdle weakness (PMID: 19461931, 20141356, 32528171). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41929). 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. 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. |
| Center for Genomic Medicine, |
RCV003984812 | SCV004801199 | likely pathogenic | Myofibrillar myopathy 2 | 2024-03-14 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV004018734 | SCV005017974 | uncertain significance | Cardiovascular phenotype | 2024-02-16 | criteria provided, single submitter | clinical testing | The p.R56W variant (also known as c.166C>T), located in coding exon 1 of the CRYAB gene, results from a C to T substitution at nucleotide position 166. The arginine at codon 56 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in the homozygous state in individuals from families affected with juvenile cataracts; however, it has also been detected in the homozygous and heterozygous states in individuals without juvenile cataracts, and has been reported as a relatively common allele in both case and control cohorts (Safieh LA et al. Mol Vis, 2009 May;15:980-4; Khan AO et al. Ophthalmic Genet, 2010 Mar;31:30-6; Cui XJ et al. Medicine (Baltimore), 2017 Jun;96:e7158). This variant has been detected in a cohort of patients with features of skeletal myopathies; however, clinical detail was not provided (Töpf A et al. Genet Med, 2020 Sep;22:1478-1488). Functional studies suggest this variant may impact some aspects of protein function; however, the physiological relevance of these findings are unclear (Raju I et al. Biochem Biophys Res Commun. 2013 Jan;430(1):107-12; Muranova LK et al. Exp Eye Res. 2020 Aug;197:108091). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| OMIM | RCV000034842 | SCV000058412 | pathogenic | Cataract 16 multiple types | 2009-05-15 | no assertion criteria provided | literature only |