Submissions for variant NM_004415.4(DSP):c.3562T>C (p.Tyr1188His)

gnomAD frequency: 0.00013  dbSNP: rs141508330

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171913	SCV000050922	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230086	SCV000288534	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000171913	SCV000576567	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect: reduced desmosomal gene expression and a prolonged APD compared to wildtype (PMID: 36868229); This variant is associated with the following publications: (PMID: 31983221, 31402444, 30975432, 30847666, 35753512, 23861362, 36868229, 27532257, 34389451, 37589201, 37652022)
Color Diagnostics, LLC DBA Color Health	RCV000777754	SCV000913717	uncertain significance	Cardiomyopathy	2023-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 1188 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). A functional study has shown that this variant causes a reduction of DSP protein expression and a prolonged action potential duration (PMID: 36868229). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 36868229) and in four individuals affected with dilated cardiomyopathy (PMID: 27532257, 30975432, 31983221). This variant has also been reported in an individual who experienced sudden cardiac arrest (PMID: 34389451), an individual who experienced sudden infant death syndrome (PMID: 37589201), and in an individual with a suspected unknown cardiomyopathy (PMID: 30847666). This variant has been identified in 22/281874 chromosomes (18/128520 non-Finnish European 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.
Illumina Laboratory Services, Illumina	RCV001161514	SCV001323400	uncertain significance	Woolly hair-skin fragility syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000185557	SCV001323401	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001161515	SCV001323402	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics	RCV000185557	SCV001530134	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-12-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002453565	SCV002615572	uncertain significance	Cardiovascular phenotype	2023-09-27	criteria provided, single submitter	clinical testing	The p.Y1188H variant (also known as c.3562T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 3562. The tyrosine at codon 1188 is replaced by histidine, an amino acid with similar properties. This alteration has also been reported in cardiomyopathy and sudden death cohorts; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Asatryan B et al. Am. J. Cardiol., 2019 06;123:2031-2038; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has been detected in an individual reported to have arrhythmogenic cardiomyopathy (van Kampen SJ et al. Stem Cell Reports. 2023 Mar;18(3):749-764). In vitro studies suggest this variant may impact protein function; however, additional evidence is needed to confirm these findings (van Kampen SJ et al. Stem Cell Reports. 2023 Mar;18(3):749-764). This amino acid position is not 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.
Fulgent Genetics, Fulgent Genetics	RCV002492683	SCV002791969	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-10-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777754	SCV003838433	uncertain significance	Cardiomyopathy	2022-03-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488414	SCV004240835	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: DSP c.3562T>C (p.Tyr1188His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250516 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (7.6e-05 vs 0.0002), allowing no conclusion about variant significance. c.3562T>C has been reported in the literature in individuals affected with DCM and in a patient with sudden cardiac arrest who also carried other potentially pathogenic variants (Mazzarotto_2020, Asatryan_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27532257, 30975432, 31983221). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003995637	SCV004823206	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 1188 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). A functional study has shown that this variant causes a reduction of DSP protein expression and a prolonged action potential duration (PMID: 36868229). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 36868229) and in four individuals affected with dilated cardiomyopathy (PMID: 27532257, 30975432, 31983221). This variant has also been reported in an individual who experienced sudden cardiac arrest (PMID: 34389451), an individual who experienced sudden infant death syndrome (PMID: 37589201), and in an individual with a suspected unknown cardiomyopathy (PMID: 30847666). This variant has been identified in 22/281874 chromosomes (18/128520 non-Finnish European 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.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185557	SCV000238441	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2015-01-08	no assertion criteria provided	research	The heterozygous variant in the DSP gene (c.3562T>C; p.Tyr1188His) is considered a variant of uncertain significance. This variant is located in a highly conserved amino acid position (to lizards) and in a moderately conserved nucleotide position. The amino acid change is non-conservative and not in a functional domain. The variant is not published in the literature but it was seen in 8 individuals in the ExAC dataset (out of 120632 alleles interrogated at this position).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000171913	SCV001743330	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000171913	SCV001917766	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171913	SCV001974976	uncertain significance	not provided		no assertion criteria provided	clinical testing