rs151115778
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_004415.4(DSP):c.3616T>A(p.Leu1206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,613,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. L1206V) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.3616T>A | p.Leu1206Ile | missense_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.3616T>A | p.Leu1206Ile | missense_variant | 23/24 | ||
DSP | NM_001008844.3 | c.3582+34T>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.3616T>A | p.Leu1206Ile | missense_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3582+34T>A | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.3616T>A | p.Leu1206Ile | missense_variant | 23/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000923 AC: 14AN: 151668Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000916 AC: 23AN: 251146Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135766
GnomAD4 exome AF: 0.0000876 AC: 128AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65AN XY: 727226
GnomAD4 genome ? AF: 0.0000923 AC: 14AN: 151668Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9AN XY: 74050
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 05, 2023 | This missense variant replaces leucine with isoleucine at codon 1206 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 26/282508 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 | Sep 20, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2017 | A variant of uncertain significance has been identified in the DSP gene. The L1206I variant has not been published as pathogenic or been reported as benign to our knowledge. The L1206I variant is not observed in large population cohorts (Lek et al., 2016). However, the L1206I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to leucine (L) are tolerated across species and where isolecuine (I) is present as the wild type in at least two species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 10, 2017 | - - |
Dilated cardiomyopathy 1S Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen | May 01, 2016 | - - |
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 | Dec 18, 2023 | This missense variant replaces leucine with isoleucine at codon 1206 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 26/282508 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. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 16, 2015 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2023 | The p.L1206I variant (also known as c.3616T>A), located in coding exon 23 of the DSP gene, results from a T to A substitution at nucleotide position 3616. The leucine at codon 1206 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an individual with dilated cardiomyopathy (Klauke B et al. PLoS One, 2017 Dec;12:e0189489). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2018 | Variant summary: DSP c.3616T>A (p.Leu1206Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 276874 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3616T>A has been reported in the literature in a DCM family segregating with a likely pathogenic (class IV) RBM20 variant, p.Ser635Cys that the authors believed to be the cause for disease (Klauke_2017). This DSP variant was classified as a VUS (class 3 variant) and was reportedly identified in all genetically tested family members in this study. We interpret this to mean that the variant was present in both affected (i.e., the RBM20 variant positive) and unaffected (i.e., the RBM20 negative) members of this DCM kindred. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
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 12, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at