Submissions for variant NM_004415.4(DSP):c.2552T>A (p.Leu851Gln)

gnomAD frequency: 0.00013  dbSNP: rs111368396

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181301	SCV000233592	uncertain significance	not provided	2024-07-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37589201, 27332903)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524989	SCV000641296	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-09-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769220	SCV000900596	uncertain significance	Cardiomyopathy	2017-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769220	SCV000904671	uncertain significance	Cardiomyopathy	2024-02-12	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 851 of the DSP protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with affected with unexplained sudden cardiac death (PMID: 27332903) and in one infant affected with sudden death (PMID: 37589201). This variant has been identified in 18/282826 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	RCV002426871	SCV002740667	uncertain significance	Cardiovascular phenotype	2024-08-20	criteria provided, single submitter	clinical testing	The p.L851Q variant (also known as c.2552T>A), located in coding exon 18 of the DSP gene, results from a T to A substitution at nucleotide position 2552. The leucine at codon 851 is replaced by glutamine, an amino acid with dissimilar properties. This variant was identified in one individual with sudden unexplained cardiac death (Bagnall RD et al. N. Engl. J. Med., 2016 Jun;374:2441-52). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002503703	SCV002814970	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	2021-08-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488434	SCV004240958	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: DSP c.2552T>A (p.Leu851Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251432 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (5.6e-05 vs 0.0002), allowing no conclusion about variant significance. c.2552T>A has been reported in the literature in individuals affected with sudden cardiac death (Bagnall_2016). These report(s) 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 publication have been ascertained in the context of this evaluation (PMID: 27332903). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003996647	SCV004823424	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 851 of the DSP protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with affected with unexplained sudden cardiac death (PMID: 27332903) and in one infant affected with sudden death (PMID: 37589201). This variant has been identified in 18/282826 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000769220	SCV005399293	uncertain significance	Cardiomyopathy	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both keratinisation disorders and ARVC (PMID: 26604139, PMID: 16917092). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete (age-dependent) penetrance has been reported for ARVC (PMID: 29062697). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (18 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated spectrin 6 domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been identified in a 16 year old sudden unexplained cardiac death patient with no structural heart defects noted on post-mortem (PMID: 27332903). Variant has four VUS entries in 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
Mayo Clinic Laboratories, Mayo Clinic	RCV000181301	SCV005412000	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing	BP4