ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3562T>C (p.Tyr1188His) (rs141508330)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171913 SCV000050922 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Invitae RCV000230086 SCV000288534 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1188 of the DSP protein (p.Tyr1188His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs141508330, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 188465). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000171913 SCV000576567 uncertain significance not provided 2017-04-27 criteria provided, single submitter clinical testing The Y1188H variant of uncertain significance in the DSP gene has been reported in one individual from an ARVC cohort, though case-specific clinical details or diagnostic criteria were not made available (Walsh et al., 2017). It has also been reported in one individual from a cohort of patients undergoing whole exome sequencing, who were not selected for a history of cardiac arrhythmia, cardiomyopathy, or sudden cardiac death (Ng et al., 2013). This variant has been identified independently and/or in conjunction with additional cardiogenetic variants in several individuals referred for either cardiomyopathy or arrhythmia genetic testing at GeneDx. So far, segregation data are absent for these individuals.The Y1188H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, Y1188H was observed in 20/126,026 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).
Color RCV000777754 SCV000913717 uncertain significance Cardiomyopathy 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the central rod domain of the DSP protein that is thought to form a dimeric coiled coil. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported in a Dutch individual affected with arrhythmogenic right ventricular cardiomyopathy (van Kampen et al, 2018). This study has also reported enhanced estrogen-related receptor alpha (ESRRA) signaling in mutant cells derived from the patient, as well as in the heart from a mouse transgenic for the mutant allele. However, clinical significance of these findings is not known. This variant has been identified in 24/276234 chromosomes (20/126026 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185557 SCV000238441 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2015-01-08 no assertion criteria provided research The heterozygous variant in the DSP gene (c.3562T>C; p.Tyr1188His) is considered a variant of uncertain significance. This variant is located in a highly conserved amino acid position (to lizards) and in a moderately conserved nucleotide position. The amino acid change is non-conservative and not in a functional domain. The variant is not published in the literature but it was seen in 8 individuals in the ExAC dataset (out of 120632 alleles interrogated at this position).

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