Submissions for variant NM_004415.4(DSP):c.5513G>A (p.Arg1838His)

gnomAD frequency: 0.00009  dbSNP: rs377715841

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181329	SCV000233626	uncertain significance	not specified	2014-05-14	criteria provided, single submitter	clinical testing	The R1838H variant in the DSP gene has been reported in one individual with DCM who also harbored a R907H variant in DSP (Garcia - Pavia P et al., 2011). This individual's parent, who also harbored the R1838H variant, had DCM with fatty infiltrate and fibrosis in the right ventricle. The authors did not report whether the parent harbored R907H. Additionally, R1838H was identified on whole genome sequencing in one individual with a family history of vascular disease and early sudden death (Ashley E et al., 2010). This individual had two other rare variants identified in the TMEM43 and MYPBC3 genes. Furthermore, R1838H was observed in only 3/8600 alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico algorithms are not consistent in their predictions but at least two concur that R1838H is damaging to the protein structure/function. However, R1838H is only a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The R1838 residue is not well conserved across species, and definitive mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Illumina Laboratory Services, Illumina	RCV000296688	SCV000465127	likely benign	Arrhythmogenic right ventricular dysplasia 8	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000351218	SCV000465128	likely benign	Lethal acantholytic epidermolysis bullosa	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000391247	SCV000465129	likely benign	Woolly hair-skin fragility syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV000458538	SCV000543284	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777694	SCV000913627	uncertain significance	Cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1838 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28288337), dilated cardiomyopathy (PMID: 21859740), hypertrophic cardiomyopathy (PMID: 30775854), unexplained intrauterine fetal death (PMID: 33762593), and in an individual with a family history of atherosclerotic vascular disease and early sudden death (PMID: 20435227). This variant has also been identified in 20/282730 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV000987653	SCV001137053	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345454	SCV002648682	uncertain significance	Cardiovascular phenotype	2018-09-10	criteria provided, single submitter	clinical testing	The p.R1838H variant (also known as c.5513G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 5513. The arginine at codon 1838 is replaced by histidine, an amino acid with highly similar properties. This variant co-occurred with a second DSP variant in a proband and parent reported to have dilated cardiomyopathy (Garcia-Pavia P et al. Heart. 2011;97:1744-52), and was also detected in an individual reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC) (Chen X et al. Forensic Sci Int. 2017;275:14-22). This variant has also been identified in individuals not known to have ARVC on review of health records (Haggerty CM et al. Genet Med. 2017;11;19(11):1245-1252), and has been detected in an exome cohort (Andreasen C et al. Eur J Hum Genet. 2013;21:918-28). In another study, this variant was detected with other variants in cardiac-related genes in an individual with family history of vascular disease and sudden death (Ashley EA et al. Lancet. 2010;375:1525-35). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181329	SCV002819852	uncertain significance	not specified	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: DSP c.5513G>A (p.Arg1838His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (7.2e-05 vs 0.0002), allowing no conclusion about variant significance. c.5513G>A has been reported in the literature in individuals affected with DCM, HCM, or unexplained intrauterine fetal death. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n=1, likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148475	SCV000190176	likely benign	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research