Submissions for variant NM_004415.4(DSP):c.6307A>G (p.Lys2103Glu)

gnomAD frequency: 0.00010  dbSNP: rs149513743

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181387	SCV000233689	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	Identified in patients with DCM in published literature; one patient harbored an additional variant in the DSP gene (PMID: 28416588, 31514951); Identified in an individual with SCD and primary myocardial fibrosis (PMID: 29915098); Identified in a patient with a clinical diagnosis of Noonan syndrome with survived cardiac arrest (PMID: 31378211); Published functional study suggests this variant is not predicted to significantly alter protein structure (PMID: 35008956); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31514951, 28416588, 26606670, 29915098, 37937776, 31378211, 35008956)
Illumina Laboratory Services, Illumina	RCV000318076	SCV000465162	uncertain significance	Woolly hair-skin fragility syndrome	2018-01-13	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	RCV001095257	SCV000465164	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-01-13	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	RCV000316774	SCV000465165	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477049	SCV000543249	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-15	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000259235	SCV000700096	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color Diagnostics, LLC DBA Color Health	RCV000777748	SCV000913710	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2103 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 28416588), in an individual affected with sudden cardiac arrest and Noonan syndrome (PMID: 31378211), and in an individual affected with sudden cardiac death due to primary myocardial fibrosis (Holmstrom 2020, dissertation, University of Oulu). This variant has also been identified in 37/282852 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.
Ambry Genetics	RCV002362836	SCV002660579	likely benign	Cardiovascular phenotype	2021-10-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV002484961	SCV002785312	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	2021-08-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181387	SCV003800206	uncertain significance	not provided	2022-04-21	criteria provided, single submitter	clinical testing	The DSP c.6307A>G; p.Lys2103Glu variant (rs149513743) has been reported two individuals with dilated cardiomyopathy (Dal Ferro 2017, Gigli 2019) and in an individual with sudden cardiac arrest and Noonan syndrome (Petrin 2019). The variant is reported in the ClinVar database (Variation ID: 180336) and is found in the non-Finnish European population with an allele frequency of 0.025% (32/129,176 alleles) in the Genome Aggregation Database. The lysine at codon 2103 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.357). Due to limited information, the clinical significance of the p.Lys2103Glu variant is uncertain at this time. References: Dal Ferro M et al. Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. Heart. 2017 Nov;103(21):1704-1710. PMID: 28416588. 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: 31514951. Petrin Z et al. Sudden cardiac arrest in the field in an 18-year-old male athlete with Noonan syndrome: case presentation and 5-year follow-up. Cardiol Young. 2019 Sep;29(9):1214-1216. PMID: 31378211.
Clinical Genomics Laboratory, Stanford Medicine	RCV001095257	SCV004801382	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2021-05-07	criteria provided, single submitter	clinical testing	•The p.Lys2103Glu variant in the DSP gene has been previously reported in 3 unrelated individuals, 1 individual with dilated cardiomyopathy, 1 individual with dilated cardiomyopathy who had a second variant of uncertain significant in this gene, and 1 individual with Noonan syndrome and sudden cardiac arrest (Del Ferro et al., 2017; Gigli et al., 2019; Petrin, Soffer and Daniels 2019). • This variant has been identified in 32/129,176 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Computational tools predict that the p.Lys2103Glu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Lys2103Glu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: none]
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000316774	SCV005398716	uncertain significance	Lethal acantholytic epidermolysis bullosa	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with a variety of DSP-related cardiac disorders (MIM#607450, 605676, 615821) and DSP-related skin disorders (MIM#609638, 612908, 607655). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance, which is age dependent for arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0115 - Variants in this gene are known to have variable expressivity for arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 37 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Plectin repeat (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been identified in patients who suffered sudden cardiac arrests and dilated cardiomyopathy. It was also one of three variants identified in a patient with stress-induced cardiomyopathy, although the causative variant was not indicated. Finally, this variant has been classified as a VUS by diagnostic laboratories in ClinVar (PMID: 31378211, 29915098, 28416588, 26606670; ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Blueprint Genetics	RCV000157206	SCV000206930	uncertain significance	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing