Submissions for variant NM_004415.4(DSP):c.5324G>T (p.Arg1775Ile)

gnomAD frequency: 0.00002  dbSNP: rs34738426

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148479	SCV000050924	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000766884	SCV000233686	uncertain significance	not provided	2021-07-15	criteria provided, single submitter	clinical testing	Identified in one heterozygous individual with woolly hair referred for exome sequencing at GeneDx; however, no cardiac-related clinical information or informative segregation data is available; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 161227; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26582918, 27535533, 31402444, 25637381, 28472724, 21723241, 23861362, 15941723, 23299917)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215521	SCV000271733	uncertain significance	not specified	2014-12-31	criteria provided, single submitter	clinical testing	The p.Arg1775Ile variant in DSP has been previously reported in 1 adult with sud den death and segregated with right ventricular and ECG abnormalities in 2 affec ted family members (Bauce 2005). This variant has also been identified in 8/1655 6 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs34738426). The affected amino acid is not well cons erved in evolution, raising the possibility that a change may be tolerated; howe ver, this is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Arg1775Ile variant is uncertain.
Invitae	RCV000460497	SCV000543250	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-18	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000677333	SCV000803592	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 8, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1-Supporting => BS1 downgraded in strength to supporting.
Fulgent Genetics, Fulgent Genetics	RCV000764660	SCV000895786	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	2021-08-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001192114	SCV001360090	uncertain significance	Cardiomyopathy	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 1775 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 four related individuals from a family (Family 151, PMID: 15941723). Only one of these individuals, a female who was diagnosed at the age of 37 year old, was affected with ventricular fibrillation and and aborted sudden death, but she did not fulfill diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy. The proband's 13 year old son, 52 year old sister and her 18 year old son (proband's nephew) were unaffected although the proband's son had positive late potentials and sister had right ventricular abnormalities (PMID: 15941723). This variant has been identified in 18/282174 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.
Baylor Genetics	RCV001332447	SCV001524775	uncertain significance	Woolly hair-skin fragility syndrome	2019-10-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000766884	SCV002542158	uncertain significance	not provided	2021-09-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766884	SCV004163055	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	DSP: PM2, BP4
CSER _CC_NCGL, University of Washington	RCV000148479	SCV000190181	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766884	SCV001739638	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766884	SCV001929158	uncertain significance	not provided		no assertion criteria provided	clinical testing