rs766505506
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004415.4(DSP):āc.1671A>Gā(p.Ile557Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I557T) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.1671A>G | p.Ile557Met | missense_variant | 13/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.1671A>G | p.Ile557Met | missense_variant | 13/24 | ||
DSP | NM_001008844.3 | c.1671A>G | p.Ile557Met | missense_variant | 13/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.1671A>G | p.Ile557Met | missense_variant | 13/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.1671A>G | p.Ile557Met | missense_variant | 13/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.1671A>G | p.Ile557Met | missense_variant | 13/24 | A2 | |||
DSP | ENST00000684395.1 | n.55A>G | non_coding_transcript_exon_variant | 1/5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251240Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135770
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461462Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727040
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2022 | Identified in a patient with DCM and in a patient with HCM in the published literature (van Lint et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 27535533) - |
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 | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
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 | Mar 28, 2023 | This missense variant replaces isoleucine with methionine at codon 557 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having dilated cardiomyopathy and in another individual suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has been identified in 2/251240 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 dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 557 of the DSP protein (p.Ile557Met). This variant is present in population databases (rs766505506, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 534278). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 10, 2023 | This missense variant replaces isoleucine with methionine at codon 557 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having dilated cardiomyopathy and in another individual suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has been identified in 2/251240 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2022 | The p.I557M variant (also known as c.1671A>G), located in coding exon 13 of the DSP gene, results from an A to G substitution at nucleotide position 1671. The isoleucine at codon 557 is replaced by methionine, an amino acid with highly similar properties. This variant was detected in two individuals from a cardiomyopathy genetic testing cohort; however, clinical details were limited, and one individual had additional cardiac variants detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at