rs112242645
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_004415.4(DSP):c.4022G>A(p.Arg1341His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R1341C) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4022G>A | p.Arg1341His | missense_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.4022G>A | p.Arg1341His | missense_variant | 23/24 | ||
DSP | NM_001008844.3 | c.3582+440G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4022G>A | p.Arg1341His | missense_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3582+440G>A | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.4022G>A | p.Arg1341His | missense_variant | 23/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152006Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250638Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135648
GnomAD4 exome AF: 0.0000540 AC: 79AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 727214
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74366
ClinVar
Submissions by phenotype
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 | Jan 11, 2024 | This missense variant replaces arginine with histidine at codon 1341 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, dilated cardiomyopathy, or stillbirth (PMID: 27532257,30615648, 32879264, Fish 2010, dissertation, University of Cape Town). This variant has also been identified in 17/282014 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 16, 2023 | This missense variant replaces arginine with histidine at codon 1341 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, dilated cardiomyopathy, or stillbirth (PMID: 27532257,30615648, 32879264, Fish 2010, dissertation, University of Cape Town). This variant has also been identified in 17/282014 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2021 | Identified in a patient with DCM in published literature (Walsh et al., 2017) and in a patient with polycystic kidney disease (PKD) who developed and died of acute cardiac failure at 8 months old; exome sequencing in this patient identified a pathogenic variant in PKD1, compound heterozygous variants in JPH2, and heterozygous variants in TTN, MAP2K2, and the R1341H variant in DSP (Miura et al., 2022); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 566448; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 32879264, 27535533) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2023 | The p.R1341H variant (also known as c.4022G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4022. The arginine at codon 1341 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts and a stillbirth cohort; however, clinical details were limited and additional alterations were identified in some cases (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Sahlin E et al. PLoS One, 2019 Jan;14:e0210017; Miura A et al. Int Heart J, 2020 Sep;61:1079-1083). 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. - |
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 23, 2021 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at