rs141508330
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004415.4(DSP):c.3562T>C(p.Tyr1188His) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,613,404 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. Y1188C) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.3562T>C | p.Tyr1188His | missense_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.3562T>C | p.Tyr1188His | missense_variant | 23/24 | ||
DSP | NM_001008844.3 | c.3562T>C | p.Tyr1188His | missense_variant | 23/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.3562T>C | p.Tyr1188His | missense_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3562T>C | p.Tyr1188His | missense_variant | 23/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.3562T>C | p.Tyr1188His | missense_variant | 23/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000119 AC: 18AN: 151814Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000758 AC: 19AN: 250516Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135430
GnomAD4 exome AF: 0.000322 AC: 470AN: 1461590Hom.: 0 Cov.: 32 AF XY: 0.000312 AC XY: 227AN XY: 727076
GnomAD4 genome ? AF: 0.000119 AC: 18AN: 151814Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6AN XY: 74104
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2020 | Identified in a patient from an ARVC cohort, though case-specific clinical details or diagnostic criteria were not made available (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 188465; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362, 27532257, 31983221, 31402444) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:3
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jan 08, 2015 | 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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 14, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 20, 2023 | This missense variant replaces tyrosine with histidine at codon 1188 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). A functional study has shown that this variant causes a reduction of DSP protein expression and a prolonged action potential duration (PMID: 36868229). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 36868229) and in four individuals affected with dilated cardiomyopathy (PMID: 27532257, 30975432, 31983221). This variant has also been reported in an individual who experienced sudden cardiac arrest (PMID: 34389451), an individual who experienced sudden infant death syndrome (PMID: 37589201), and in an individual with a suspected unknown cardiomyopathy (PMID: 30847666). This variant has been identified in 22/281874 chromosomes (18/128520 non-Finnish European 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 24, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2023 | Variant summary: DSP c.3562T>C (p.Tyr1188His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250516 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (7.6e-05 vs 0.0002), allowing no conclusion about variant significance. c.3562T>C has been reported in the literature in individuals affected with DCM and in a patient with sudden cardiac arrest who also carried other potentially pathogenic variants (Mazzarotto_2020, Asatryan_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 27532257, 30975432, 31983221). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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 tyrosine with histidine at codon 1188 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). A functional study has shown that this variant causes a reduction of DSP protein expression and a prolonged action potential duration (PMID: 36868229). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 36868229) and in four individuals affected with dilated cardiomyopathy (PMID: 27532257, 30975432, 31983221). This variant has also been reported in an individual who experienced sudden cardiac arrest (PMID: 34389451), an individual who experienced sudden infant death syndrome (PMID: 37589201), and in an individual with a suspected unknown cardiomyopathy (PMID: 30847666). This variant has been identified in 22/281874 chromosomes (18/128520 non-Finnish European 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. - |
Lethal acantholytic epidermolysis bullosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Woolly hair-skin fragility syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2023 | The p.Y1188H variant (also known as c.3562T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 3562. The tyrosine at codon 1188 is replaced by histidine, an amino acid with similar properties. This alteration has also been reported in cardiomyopathy and sudden death cohorts; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Asatryan B et al. Am. J. Cardiol., 2019 06;123:2031-2038; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has been detected in an individual reported to have arrhythmogenic cardiomyopathy (van Kampen SJ et al. Stem Cell Reports. 2023 Mar;18(3):749-764). In vitro studies suggest this variant may impact protein function; however, additional evidence is needed to confirm these findings (van Kampen SJ et al. Stem Cell Reports. 2023 Mar;18(3):749-764). This amino acid position is not 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 | Oct 11, 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 | Jan 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at