Submissions for variant NM_004415.4(DSP):c.8467C>G (p.Pro2823Ala) (rs142717240)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000038106	SCV000061772	likely benign	not specified	2018-12-31	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000587297	SCV000228148	uncertain significance	not provided	2015-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000587297	SCV000233650	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing	The P2823A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI Exome Sequencing Project reports P2823A was observed in 8/8600 (0.1%) alleles from individuals of European background. The P2823A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is possibly damaging to the protein structure/function. A missense mutation in a nearby residue (R2834H) has been reported in association with ARVC, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina	RCV000392016	SCV000465258	likely benign	Ectodermal dysplasia skin fragility syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000302977	SCV000465259	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000357526	SCV000465260	likely benign	Skin fragility woolly hair syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000405429	SCV000465261	likely benign	Epidermolysis bullosa, lethal acantholytic	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000477077	SCV000543252	uncertain significance	Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8	2018-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline with alanine at codon 2823 of the DSP protein (p.Pro2823Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs142717240, ExAC 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 44969). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America	RCV000587297	SCV000698452	likely benign	not provided	2017-03-13	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.8467C>G (p.Pro2823Ala) variant involves the alteration of a conserved nucleotide that 4/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 40/120732 control chromosomes (1 homozygote) at a frequency of 0.0003313, which is approximately 33 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this variant is likely a benign polymorphism. Multiple clinical diagnostic laboratories/reputable databases have cited the variant with conflicting classifications "likely benign" or "uncertain significance." In addition, the variant of interest has not, to our knowledge, been reported in affected individuals via publications. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as "likely benign."
Ambry Genetics	RCV000619198	SCV000736855	uncertain significance	Cardiovascular phenotype	2017-03-23	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
Color	RCV000771367	SCV000903662	uncertain significance	Cardiomyopathy	2018-06-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the C-terminal end of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in an individual affected with cardiovascular disorders in the literature. This variant has been identified in 85/274938 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.