rs200484060
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001943.5(DSG2):c.1592T>G(p.Phe531Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F531S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.1592T>G | p.Phe531Cys | missense_variant | 11/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.1058T>G | p.Phe353Cys | missense_variant | 12/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.1592T>G | p.Phe531Cys | missense_variant | 11/15 | 1 | NM_001943.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000561 AC: 14AN: 249384Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135290
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727234
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74490
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 12, 2022 | This missense variant replaces phenylalanine with cysteine at codon 531 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A study using a homozygous knock-in mouse model has reported that this variant results in a cardiomyopathy phenotype with left ventricular systolic dysfunction (Wang et. al, 2019). This variant has been reported in over ten individuals of East Asian ancestry affected with arrhythmogenic right ventricular cardiomyopathy, either in homozygous or compound heterozygous state (PMID: 18632414, 23514727, 24125834, 25765472, 28578331, 30129429, 30177324, 30454721, 31183845, 31645976; Wang et. al, 2019, https://doi.org/10.1093/eurheartj/ehz746.0202). In these families, over 20 heterozygous family members were reported to be unaffected, while several heterozygotes were reported to be affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or sudden unexplained death. This variant has also been identified in 16/280790 chromosomes (16/19518 East Asian chromosomes, 0.0819%) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmogenic cardiomyopathy 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 22, 2018 | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces phenylalanine with cysteine at codon 531 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A study using a homozygous knock-in mouse model has reported that this variant results in a cardiomyopathy phenotype with left ventricular systolic dysfunction (Wang et. al, 2019). This variant has been reported in over ten individuals of East Asian ancestry affected with arrhythmogenic right ventricular cardiomyopathy, either in homozygous or compound heterozygous state (PMID: 18632414, 23514727, 24125834, 25765472, 28578331, 30129429, 30177324, 30454721, 31183845, 31645976; Wang et. al, 2019, https://doi.org/10.1093/eurheartj/ehz746.0202). In these families, over 20 heterozygous family members were reported to be unaffected, while several heterozygotes were reported to be affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or sudden unexplained death. This variant has also been identified in 16/280790 chromosomes (16/19518 East Asian chromosomes, 0.0819%) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmogenic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 23, 2011 | The Phe531Cys variant (DSG2) has been reported as a homozygous variant in one Ta wainese individual with ARVD and was absent in 200 control chromosomes (Yu 2008) . Phenylalanine (Phe) at position 531 is highly conserved across evolutionarily distant species, increasing the likelihood that a change would not be tolerated. Computational tools are mixed on the predicted impact to the protein (PolyPhen 2 & SIFT = pathogenic, AlignGVGD = benign), though the accuracy of these tools i s unknown. In summary, the clinical significance of this variant cannot be deter mined at this time. - |
Arrhythmogenic right ventricular dysplasia 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 531 of the DSG2 protein (p.Phe531Cys). This variant is present in population databases (rs200484060, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 18632414, 23514727, 24238504, 25765472, 28578331, 28878402, 30454721, 30830208, 31645976). ClinVar contains an entry for this variant (Variation ID: 44283). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2018 | The F531C variant of uncertain significance in the DSG2 gene has been previously reported in either the heterozygous or homozygous state in several Asian individuals with definite or suspected ARVC (Yu et al., 2008; Bao et al., 2013a; Bao et al., 2013b; Ohno et al., 2013); however, detailed clinical information and segregation data were not provided for most probands. In addition, one of these probands, who inherited the F531C variant from his father, was also found to be homozygous for a second variant in the DSP gene (Ohno et al., 2013). Upon evaluation, both of his parents were diagnosed with possible ARVC and were found to be heterozygous for this DSP variant (Ohno et al., 2013). Furthermore, F531C has been identified in the homozygous state in two other individuals referred for cardiac genetic testing at GeneDx. This variant has also been observed in approximately 0.1% of alleles from individuals of East Asian background in the Exome Aggregation Consortium, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). Nevertheless, F531C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. Moreover, in silico analysis predicts F531C is probably damaging to the protein structure/function. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2019 | The c.1592T>G (p.F531C) alteration is located in exon 11 (coding exon 11) of the DSG2 gene. This alteration results from a T to G substitution at nucleotide position 1592, causing the phenylalanine (F) at amino acid position 531 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at