Submissions for variant NM_004415.4(DSP):c.3646A>G (p.Ile1216Val)

gnomAD frequency: 0.00011  dbSNP: rs199795359

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171915	SCV000055167	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000038029	SCV000233606	uncertain significance	not specified	2013-03-08	criteria provided, single submitter	clinical testing	p.Ile1216Val (ATT>GTT): c.3646 A>G in exon 23 of the DSP gene (NM_004415.2). The Ile1216Val variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ile1216Val results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is conserved across species. The Ile1216Val variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, Ile1216Val was observed in 0.4% of Asian alleles in the 1000 Genomes database. In silico algorithms are not consistent in their predictions but at least two concur that Ile1216Val is benign to the protein structure/function. In addition, mutations in nearby residues have not been reported (van der Zwaag P et al., 2009) indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Ile1216Val is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Ambry Genetics	RCV000247902	SCV000320258	likely benign	Cardiovascular phenotype	2018-04-10	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.
Invitae	RCV001087636	SCV000555777	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182251	SCV001347639	likely benign	Cardiomyopathy	2018-11-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001182251	SCV002043291	benign	Cardiomyopathy	2021-05-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038029	SCV000061695	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing