Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000034838 | SCV000962324 | uncertain significance | Dilated cardiomyopathy 1II | 2022-06-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 157 of the CRYAB protein (p.Arg157His). This variant is present in population databases (rs141638421, gnomAD 0.06%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 16483541). ClinVar contains an entry for this variant (Variation ID: 41925). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CRYAB function (PMID: 16483541, 19282282, 23194663). 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. |
| Ambry Genetics | RCV002336111 | SCV002635843 | uncertain significance | Cardiovascular phenotype | 2022-12-12 | criteria provided, single submitter | clinical testing | The p.R157H variant (also known as c.470G>A), located in coding exon 3 of the CRYAB gene, results from a G to A substitution at nucleotide position 470. The arginine at codon 157 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in an individual with familial dilated cardiomyopathy who had mild symptoms and a later age of onset (Inagaki N et al. Biochem. Biophys. Res. Commun., 2006 Apr;342:379-86). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). Functional studies suggest this variant impacts the interaction between alpha-B crystallin and titin; however, the clinical impact of these findings is uncertain (Inagaki N et al. Biochem. Biophys. Res. Commun., 2006 Apr;342:379-86; Zhu Y et al. J. Biol. Chem., 2009 May;284:13914-23; Raju I et al. Biochem. Biophys. Res. Commun., 2013 Jan;430:107-12; Huang Y et al. J. Biol. Chem., 2016 May;291:11030-41). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002490468 | SCV002796333 | uncertain significance | Myofibrillar myopathy 2; Cataract 16 multiple types; Fatal infantile hypertonic myofibrillar myopathy; Dilated cardiomyopathy 1II | 2022-02-01 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000034838 | SCV000058408 | pathogenic | Dilated cardiomyopathy 1II | 2006-04-07 | no assertion criteria provided | literature only |