Submissions for variant NM_004415.4(DSP):c.273+5G>A

gnomAD frequency: 0.00031  dbSNP: rs200473206

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150557	SCV000197788	uncertain significance	not specified	2019-01-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.273+5G>A variant in DSP has been reported in 1 individual with adolescent-onset VT, 1 individual with DCM, 1 individual with sinus bradycardia, 1 compound heterozygous individual with unspecified cardiomyopathy, and at least 3 individuals with ARVC (Basso 2006, Bauce 2011, Dal Ferra 2017, Mezzano 2016, Rigato 2013, te Rijdt 2017, LMM data). This variant has also been reported in ClinVar (Variation ID 163237) and has been identified in 68/125966 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200473206). This variant is located in the 5' splice region. Computational tools suggest a possible impact to splicing. However, analysis of RNA from patients carrying this variant did not identify aberrant transcripts (Basso 2006), which may indicate that splicing is not impacted. Alternatively, this may be the result of RNA degradation, which is a frequent consequence of abnormal splicing. In summary, the clinical significance of the c.273+5G>A variant is uncertain.
GeneDx	RCV000589518	SCV000233561	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for genetic testing at GeneDx, but segregation data are limited or absent at this time; Published cDNA analysis did not yield aberrant transcripts; the authors suggest this may be due to nonsense-mediated decay of the variant allele, although detection of only the wild-type allele would also occur if this variant did not affect splicing (Basso et al., 2006); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as c.542+5 G>A and IVS2+5 G>A; This variant is associated with the following publications: (PMID: 28759816, 30398466, 21723241, 26138720, 16774985, 24070718, 27097650, 28074886, 18382419, 28416588, 34426522, 30847666, 31514951, 31737537, 32277046, 31402444, 32372669)
Invitae	RCV000232421	SCV000288532	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the DSP gene. It does not directly change the encoded amino acid sequence of the DSP protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200473206, gnomAD 0.05%). This variant has been observed in individual(s) with autosomal dominant arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy or sudden infant death syndrome, and/or autosomal recessive Carvajal syndrome (PMID: 16774985, 21723241, 28074886; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.542+5G>A. ClinVar contains an entry for this variant (Variation ID: 163237). Studies have shown that this variant alters DSP gene expression (PMID: 34290054). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (PMID: 16774985, 34290054). 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239152	SCV000297154	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-08-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150557	SCV000698427	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: DSP c.273+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and one predicts the variant weakens a 5' donor site. When mRNA transcripts from patient cells were examined, the variant did not appear to impact splicing, although very little protein was produced from the transcript even when cells were treated with NMD and protease inhibitors (Bliley_2021). The variant allele was found at a frequency of 0.00028 in 282064 control chromosomes (gnomAD, Basso_2006, Rigato_2013), predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.273+5G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Rigato_2013, van Lint_2019, Gigli_2019, Surmacz_2018, Marschall_2019, van Wijngaarden_2020, Bliley_2021). These data indicate that the variant may be associated with disease. Additional experiments using a 3D-engineeered heart tissue contractile shortening assay showed that the variant produced less than half of the DSP protein seen in controls and approximately half of the engineered heart tissues broke after removal from the culture wells. Those that could be assayed showed elevated diastolic stress and stretching of the engineered tissue (Bliley_2021). Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000776291	SCV000911583	uncertain significance	Cardiomyopathy	2023-01-18	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 2 of the DSP gene. Computational splicing tools suggest that this variant may impact RNA splicing. An RNA study performed with cells from a carrier has not detected aberrant transcripts and showed only the wild-type transcript (PMID: 16774985; variant described as c.542+5G>A). This observation suggests that the variant does not impact splicing or may be the result of degradation of the aberrant transcripts. This variant has been reported in four individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16774985, 21723241, Shestak et al. 2021, doi:10.15829/1560-4071-2021-4692) and in one individual afffected with dilated cardiomyopathy (PMID: 32826072). This variant has also been reported in compound heterozygous state with truncating variants in an individual affected with arrhythmogenic cardiomyopathy (PMID: 34290054) and in three unrelated individuals affected with Carvajal syndrome (OMIM 605676) (PMID: 34026522, Hoorntje et al. 2021, doi: 10.1101/2021.10.16.21264154). This variant occurs at an elevated frequency in the general population and has been identified in 79/281264 chromosomes (67/128380 non-Finnish European chromosomes) 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	RCV001160815	SCV001322644	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162435	SCV001324388	uncertain significance	Lethal acantholytic epidermolysis bullosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162436	SCV001324389	uncertain significance	Woolly hair-skin fragility syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776291	SCV001333548	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433645	SCV002743648	likely benign	Cardiovascular phenotype	2021-12-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002492553	SCV002797572	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	2022-04-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589518	SCV003800226	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	The DSP c.273+5G>A variant (rs200473206), also known as c.542+5G>A, is reported in the literature in individuals affected with arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy (Basso 2006, Bauce 2011, Gigli 2019). This variant is reported in ClinVar (Variation ID: 163237), and is found in the non-Finnish European population with an allele frequency of 0.05% (67/128380 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.273+5G>A variant is uncertain at this time. References: Basso et al. Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies. Eur Heart J. 2006; 27(15): 1847-1854. PMID: 16774985. Bauce et al. Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations. Heart Rhythm. 2011; 8(11): 1686-1695. PMID: 21723241. Gigli M et al. Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2019 Sep 17;74(11):1480-1490. PMID: 31514950731.
New York Genome Center	RCV001160815	SCV004176046	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2023-05-04	criteria provided, single submitter	clinical testing	The c.273+5G>A variant has previously been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and sinus bradycardia [PMID: 16774985, 21723241, 28416588, 27097650, 24070718, 28759816, 30847666, 31514951, 30398466,32277046, 34290054]. Multiple independent laboratories have deposited this variant as Variant of Uncertain Significance in the ClinVar database (Variation ID:163237). The c.273+5G>A variant is observed in 163 alleles (0.027% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8). The c.273+5G>A variant is located in the splice region after exon 2 of this 24-exon gene and is predicted to affect mRNA splicing (Splice AI =0.670 and TraP score = 0.902). The cDNA analysis of lymphocyte RNA from an individual carrying the c.273+5G>A revealed no aberrant transcripts suggesting a nonsense-mediated mRNA decay of the aberrant transcripts [PMID: 16774985]. In another study, the analysis did not reveal alternative mRNA splicing in hiPSC-derived cardiomyocytes from an individual carrying the c.273+5G>A and c.6687delA [PMID: 34290054]. Based on available evidence this c.273+5G>A variant identified in DSP is classified as a Variant of Uncertain Significance.
Blueprint Genetics	RCV000157211	SCV000206935	uncertain significance	Primary dilated cardiomyopathy; Long QT syndrome	2014-09-29	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157212	SCV000206936	uncertain significance	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing