6-7576964-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004415.4(DSP):āc.2799G>Cā(p.Leu933Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,612,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L933L) has been classified as Likely benign.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.2799G>C | p.Leu933Phe | missense_variant | 20/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2799G>C | p.Leu933Phe | missense_variant | 20/24 | ||
DSP | NM_001008844.3 | c.2799G>C | p.Leu933Phe | missense_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2799G>C | p.Leu933Phe | missense_variant | 20/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2799G>C | p.Leu933Phe | missense_variant | 20/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2799G>C | p.Leu933Phe | missense_variant | 20/24 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250856Hom.: 0 AF XY: 0.0000885 AC XY: 12AN XY: 135562
GnomAD4 exome AF: 0.000107 AC: 156AN: 1460824Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 79AN XY: 726638
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74330
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 23, 2023 | This missense variant replaces leucine with phenylalanine at codon 933 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). This variant has been identified in 21/282260 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 | Jan 08, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 11, 2017 | The p.Leu933Phe variant in DSP has been reported in 1 individual with ARVC (Wals h 2016). This variant has also been reported in ClinVar (Variation ID 265104). T his variant has been identified in 8/65790 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372922674). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, the clinical signific ance of the p.Leu933Phe variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2021 | Observed in an individual with ARVC and classified as a variant of unknown pathogenicity in the published literature (Walsh et al., 2017; Ye et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 265104; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27532257, 27535533, 31402444) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2023 | The p.L933F variant (also known as c.2799G>C), located in coding exon 20 of the DSP gene, results from a G to C substitution at nucleotide position 2799. The leucine at codon 933 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was identified in a cohort that underwent genetic testing for arrhythmogenic right ventricular cardiomyopathy; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). 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 | Nov 01, 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 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at