Submissions for variant NM_004415.4(DSP):c.5881G>A (p.Val1961Ile)

gnomAD frequency: 0.00001  dbSNP: rs368869076

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181335	SCV000233632	uncertain significance	not provided	2012-08-30	criteria provided, single submitter	clinical testing	p.Val1961Ile (GTT>ATT): c.5881 G>A in exon 24 of the DSP gene (NM_004415.2). The Val1961Ile variant in the DSP gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Val1961Ile results in a conservative substitution of one non-polar amino acid for another at a residue that is conserved across mammal species, however Isoleucine is normally present at this position in some lower species. As a result, in silico analysis predicts the Val1961Ile variant likely has a benign effect on the protein structure/function. In addition, no missense mutations have been reported in this region of the DSP gene to date, indicating this region of the protein may tolerate change (Van der Zwaag P et al., 2009). However, the NHLBI ESP Exome Variant Server reports Val1961Ile was not observed with a significant frequency in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, the clinical significance of the Val1961Ile variant in the DSP gene is currently unknown. The variant is found in ARVC panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641808	SCV000763458	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179620	SCV001344328	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1961 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 at least one individual affected with hypertrophic cardiomyopathy (PMID: 23396983, 25351510). This variant has been identified in 5/251098 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	RCV002354470	SCV002652825	likely benign	Cardiovascular phenotype	2024-02-01	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001179620	SCV004240539	benign	Cardiomyopathy	2023-05-17	criteria provided, single submitter	clinical testing