Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001175933 | SCV001339744 | uncertain significance | Cardiomyopathy | 2023-01-27 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 2375 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs the binding of the DSP protein to epidermal keratins and the muscle-specific intermediate filament desmin as well as the targeting of the protein to the intermediate filament cytoskeleton in transfected cells (PMID: 29878302, 35008956). This variant has been identified in a homozygous state in an individual from a Muslim-Arab family affected with familial autosomal recessive arrhythmogenic right ventricular cardiomyopathy, woolly hair and skin disorder (PMID: 12875771). Heterozygous individuals from this family were not affected. This variant has been identified in a homozygous state in a Kuwaiti individual affected with a localized form of autosomal recessive epidermolysis bullosa with wooly hair (PMID: 30011071). This variant has been identified in compound heterozygosity with a variant of uncertain clinical significance in two pediatric siblings affected with Carvajal syndrome, presenting with dilated cardiomyopathy, woolly hair and keratoderma. Both parents of these individuals were asymptomatic heterozygous carriers (PMID: 30944905). This variant has been identified in 2/31394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been associated with autosomal recessive conditions, however, the available evidence is insufficient to conclusively determine the pathogenicity of this variant in autosomal dominant cardiomyopathy. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Invitae | RCV002558797 | SCV003284471 | likely pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2022-10-21 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects DSP function (PMID: 29878302). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 918368). This missense change has been observed in individuals with DSP-related conditions (PMID: 12875771, 30944905). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2375 of the DSP protein (p.Gly2375Arg). |
| Ambry Genetics | RCV003284016 | SCV004007845 | likely pathogenic | Cardiovascular phenotype | 2023-06-08 | criteria provided, single submitter | clinical testing | The p.G2375R variant (also known as c.7123G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 7123. The glycine at codon 2375 is replaced by arginine, an amino acid with dissimilar properties. This variant (in addition to c.7123G>C also resulting in p.G2375R) has been detected in the homozygous state in a proband with arrhythmogenic right ventricular cardiomyopathy, woolly hair, skin disorder, and family history of sudden death in relatives with similar skin and hair findings. Heterozygous carriers from the family were reportedly unaffected (Alcalai R et al. J Am Coll Cardiol, 2003 Jul;42:319-27). This variant has also been detected in the homozygous state in a proband with epidermolysis bullosa simplex and woolly hair (Nanda A et al. Int J Dermatol, 2018 Sep;57:1058-1067). This variant has been seen in the compound heterozygous state in trans with a second DSP variant with Carvajal syndrome, woolly hair, keratoderma, and dilated cardiomyopathy requiring transplant. A sibling with both variants had similar skin and hair findings (Yermakovich D et al. Acta Myol, 2018 Dec;37:263-266). Functional studies have indicated that this variant may impact normal protein function, including protein binding interactions (Favre B et al. Br J Dermatol, 2018 Sep;179:797-799; Mohammed F et al. Int J Mol Sci, 2022 Jan;23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |