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| Dilated and arrhythmogenic cardiomyopathy v4.8 | DSG2 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877). Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877). Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis. Below are reported cases with biallelic variants and dilated cardiomyopathy: PMID:18678517 (2008) reported a single index case with dilated cardiomyopathy and carried a homozygous DSG2 p.Val55Met/ p.Val56Met variant, with an affected father and an asymptomatic mother both identified as heterozygous carriers. A broader cohort screen of 538 idiopathic DCM patients found 13 additional heterozygous carriers versus 3 in 617 controls. PMID:33949662 (2021) reported the identification of a homozygous p.Arg119Ter variant in a patient with juvenile-onset severe biventricular heart failure, for which iPSC-cardiomyocyte modeling showed disrupted desmosome deposition and abnormal intercalated discs. |
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| Dilated and arrhythmogenic cardiomyopathy v2.17 | FKRP |
Achchuthan Shanmugasundram changed review comment from: PMID:32914449 reviewed 56 patients with limb-girdle muscular dystrophy and biallelic FKRP variants, of which 45% of patients had dilated cardiomyopathy as part of the phenotype with a median age of 54 years for patients homozygous for the common founder c.826C>A, compared to 18 years of age for other variants. Dilated cardiomyopathy was also reported as part of the LGMD phenotype in both OMIM (MIM #607155) and Gene2Phenotype.; to: As reviewed by Oliver Watkinson, the limb-girdle muscular dystrophy phenotype caused by biallelic FKRP variants includes dilated cardiomyopathy as part of the phenotype. PMID:32914449 reviewed 56 patients with limb-girdle muscular dystrophy and biallelic FKRP variants, of which 45% of patients had dilated cardiomyopathy as part of the phenotype with a median age of 54 years for patients homozygous for the common founder c.826C>A, compared to 18 years of age for other variants. There were also a number of cases reported with dilated cardiomyopathy being the presenting condition and preceding overt skeletal muscle disease as noted by Oliver Watkinson including the recent case that he has seen in hospital. Dilated cardiomyopathy was also reported as part of the LGMD phenotype in both OMIM (MIM #607155) and Gene2Phenotype. |
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| Dilated and arrhythmogenic cardiomyopathy v1.21 | MYLK3 |
Ivone Leong gene: MYLK3 was added gene: MYLK3 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature Q2_21_rating tags were added to gene: MYLK3. Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709; 30690923 Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy, MONDO:0005021 Review for gene: MYLK3 was set to GREEN Added comment: This gene is also on the Cardiomyopathies - including childhood onset (Version 1.35) as an Amber gene with a recommendation of promoting to Green. This gene is not associated with a phenotype on OMIM or Gene2Phenotype. PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children. Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive. PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM. PMID: 32870709 describes three consanguineous families with homozygous variants in this gene. Review from Zornitza Stark: "Rating: I don't know Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models. Sources: Literature Created: 16 Apr 2021, 9:24 a.m." There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review. Sources: Literature |
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| Dilated and arrhythmogenic cardiomyopathy v1.12 | NRAP |
Ivone Leong gene: NRAP was added gene: NRAP was added to Dilated cardiomyopathy - adult and teen. Sources: Literature Q2_21_rating tags were added to gene: NRAP. Mode of inheritance for gene: NRAP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRAP were set to 30384889; 33534821; 28611399; https://doi.org/10.1101/2020.10.12.20211474 Phenotypes for gene: NRAP were set to Dilated cardiomyopathy, MONDO:0005021 Review for gene: NRAP was set to GREEN Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases of patients with variants in this gene and having DCM. https://doi.org/10.1101/2020.10.12.20211474 also describes a CRISPR knockout zebrafish which had a cardiac phenotype. Therefore, there is enough evidence to support a gene-disease association and this gene is recommended to be promoted Green at the next panel review. Sources: Literature |
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| Dilated and arrhythmogenic cardiomyopathy v1.9 | SLC6A6 |
Ivone Leong gene: SLC6A6 was added gene: SLC6A6 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature watchlist tags were added to gene: SLC6A6. Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034; 17875433; 20804595 Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy Review for gene: SLC6A6 was set to AMBER Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 3 unrelated cases with early retinal degeneration and only 2 cases had DCM (PMID: 31903486 and 29886034). The case described in PMID: 29886034 did not report any segregation results for the affected individual with DCM. The case described in 29886034, affected individuals were treated with taurine for 2 years and the cardiomyopathy was corrected. The mouse model (PMID: 20804595) is a KO taurine transporter showed a cardiac. Sources: Literature |
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| Dilated and arrhythmogenic cardiomyopathy v0.52 | DES | Ivone Leong edited their review of gene: DES: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.44 | DES | Matthew Edwards reviewed gene: DES: Rating: GREEN; Mode of pathogenicity: None; Publications: 19181099; Phenotypes: OMIM: 604765 Cardiomyopathy, dilated, 1I, OMIM: 601419 Myopathy, myofibrillar, 1; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.44 | DES | Matthew Edwards Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.44 | DES | Matthew Edwards reviewed gene: DES: Rating: ; Mode of pathogenicity: None; Publications: 19181099 (review); Phenotypes: OMIM: 604765 Cardiomyopathy, dilated, 1I, OMIM: 601419 Myopathy, myofibrillar, 1; Mode of inheritance: None; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.35 | DES | Ivone Leong Classified gene: DES as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.35 | DES | Ivone Leong Added comment: Comment on list classification: DES is a green gene on the Arrhythmogenic cardiomyopathy (code: 134, version 1.25). It has been promoted from amber to green in this panel as the GMS Cardiology Specialist Group decided that all green genes that are present on the Arrhythmogenic cardiomyopathy panel should also be green on this panel because of the overlap in clinical presentation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.35 | DES | Ivone Leong Gene: des has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.10 | DES | Ellen McDonagh Classified gene: DES as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.10 | DES | Ellen McDonagh Added comment: Comment on list classification: This gene appears on 3/4 gene lists submitted from GLHs, however has a Red review from one of these labs and therefore demoted to Amber for further discussion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.10 | DES | Ellen McDonagh Gene: des has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v0.0 | DES |
Ellen McDonagh gene: DES was added gene: DES was added to Dilated cardiomyopathy - adult and teen. Sources: Emory Genetics Laboratory,Expert list,North West GLH,Expert Review Green,London South GLH,Illumina TruGenome Clinical Sequencing Services,Radboud University Medical Center, Nijmegen,South West GLH,UKGTN Mode of inheritance for gene: DES was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: DES were set to 20186049; 27532257 Phenotypes for gene: DES were set to Scapuloperoneal syndrome, neurogenic, Kaeser type (181400); Myopathy, myofibrillar, 1 (601419); Cardiomyopathy, dilated, 1I, (604765); Cardiomyopathy, dilated, 1I, |
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