rs574637009
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004415.4(DSP):c.6248G>A(p.Arg2083His) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2083C) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.6248G>A | p.Arg2083His | missense_variant | 24/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.4919G>A | p.Arg1640His | missense_variant | 24/24 | ||
DSP | NM_001008844.3 | c.4451G>A | p.Arg1484His | missense_variant | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.6248G>A | p.Arg2083His | missense_variant | 24/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.4451G>A | p.Arg1484His | missense_variant | 24/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.4919G>A | p.Arg1640His | missense_variant | 24/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251246Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135806
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727238
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74440
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 27, 2016 | p.Arg2083His (c.6248G>A) in DSP gene (NM_004415.2) Seen in a patient in our center with recurrent unexplained ventricular tachycardia and ventricular fibrillation as well as intellectual disability. Given the novel nature of this variant, we consider this missense variant to be a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The DSP gene has been reported in OMIM to be associated with the following phenotypes: arrhythmogenic right ventricular dysplasia 8, dilated cardiomyopathy with wooly hair and keratoderma, and dilated cardiomyopathy with woolly hair, keratoderma and tooth agenesis. Per our own searches and the lab report, it appears the variant has not been reported in individuals with heart problems. The variant has been seen in 1 of 60,300 individuals. It was reported in 1 individual in ExAC. Specifically, the variant has been observed in the following ethnicity: African, 1/5,069. The population frequency of this variant is 0.001%. The phenotype of this individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Another variant in the same location, c.6248C>T (p.Arg2083Cys), has been reported in 5 individuals in ExAC. Specifically, the variant has been observed in the following ethnicities: African: 1/5,069, European (non-Finnish): 4/33,123. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2013 | p.Arg2083His (CGT>CAT): c.6248 G>A in exon 24 of the DSP gene (NM_004415.2). The Arg2083His variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg2083His results in a conservative amino acid substitution of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Arg2083His is damaging to the protein structure/function. The Arg2083His variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with ARVC, indicating this region of the protein may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Arg2083His is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s). - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with histidine at codon 2083 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 an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has not been identified 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 31, 2023 | This missense variant replaces arginine with histidine at codon 2083 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 an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has not been identified 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2024 | The c.6248G>A (p.R2083H) alteration is located in exon 24 (coding exon 24) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 6248, causing the arginine (R) at amino acid position 2083 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at