18-31536370-T-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_StrongBS1_SupportingBS2
The NM_001943.5(DSG2):āc.1592T>Gā(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).
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
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
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. 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. However, some evidence exists suggesting that this variant may be a common benign variant in the population and the biallelic affected individuals reported in the literature may carry another variant that could explain the observed phenotype: In one study that reported 3 homozygous individuals affected with arrhythmogenic cardiomyopathy, a potentially pathogenic covariant was observed in the DSP, SCN5A and MYH7 gene in each of the three probands (PMID: 39253717). In addition, this variant occurs at a high allele frequency in the East Asian population (16/19518 East Asian chromosomes; 0.0819%) 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. -
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Arrhythmogenic right ventricular cardiomyopathy Uncertain:1Benign:1
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. -
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Cardiovascular phenotype Pathogenic:1
The p.F531C variant (also known as c.1592T>G), located in coding exon 11 of the DSG2 gene, results from a T to G substitution at nucleotide position 1592. The phenylalanine at codon 531 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in the homozygous state in individuals of Asian background with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in at least one family; however, when detected in the heterozygous state, additional cardiac variants were detected and/or clinical details were limited (Yu CC et al. J. Formos Med Assoc. 2008;107:548-58; Bao J et al. Circ Cardiovasc Genet. 2013;6:552-6; Ohno S et al. Circ J. 2013;77:1534-42; Zhou X et al. Eur J Med Genet. 2015;58(4):258-65; Lin Y et al. Cardiology. 2017;138:41-54; Zhang B et al. BMC Med. 2024 Sep 4;22(1):361). Heterozygous family members have been reported to be unaffected or to have only mild clinical features consistent with ARVC (Lin Y et al. J Electrocardiol , 2018 Jun;51:837-843; Chen L et al. Int. J. Cardiol., 2019 Jan;274:263-270; Chen X et al. Hum Genome Var, 2019 Aug;6:38). An in vivo knock-in mouse model showed affected mice in the homozygous state; however, heterozygous mice were unaffected (Zhang B et al. BMC Med. 2024 Sep 4;22(1):361). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Although evidence suggests that this alteration may be pathogenic when found in the homozygous state, supporting evidence for a role in autosomal dominant ARVC is limited. Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive ARVC; however, the clinical significance of this alteration with respect to autosomal dominant ARVC remains unclear. -
not specified Uncertain:1
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
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). Invitae Evidence 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 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
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at