ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3862A>C (p.Lys1288Gln) (rs138907450)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620854 SCV000735974 uncertain significance Cardiovascular phenotype 2017-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000771831 SCV000904544 uncertain significance Cardiomyopathy 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the central rod domain of the DSP protein that is thought to form a dimeric coiled coil. 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834) and in an individual affected with primary electrical disease (PMID: 28341588). This variant has also been identified in 71/276710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723628 SCV000331395 uncertain significance not provided 2015-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000723628 SCV000233611 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing The K1288Q variant of uncertain significance in the DSP gene has been reported in one Chinese individual with ARVC and in one individual of unknown ethnicity with primary electric disease (PED) (Bao et al., 2013; Proost et al., 2017). The individual with PED was also reported to harbor a variant in the DSG2 gene (Proost et al., 2017). In addition, K1288Q has been identified both independently of and in conjunction with additional cardiogenetic variants in multiple unrelated individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The K1288Q variant is observed in 10/18860 (0.05%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). The K1288Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000403440 SCV000465006 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000301942 SCV000465007 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000342008 SCV000465008 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000404310 SCV000465009 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000459782 SCV000543227 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 1288 of the DSP protein (p.Lys1288Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs138907450, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy and in an individual with unspecified cardiac arrhythmia (PMID: 24125834, 28341588). ClinVar contains an entry for this variant (Variation ID: 178030). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The glutamine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154713 SCV000204393 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000723628 SCV000925072 uncertain significance not provided 2017-01-09 no assertion criteria provided provider interpretation Given the lack of case data on this variant and its relatively high prevalence in population databases, we consider this variant a variant of uncertain significance, likely benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data available for this variant. The variant has been seen in at least 1 unrelated case of arrhythmogenic right ventricular cardiomyopathy (ARVC) (not including this patient's family). The p.Lys1288Gln variant is present in ClinVar. It has been classified as a variant of uncertain significance by LMM, GeneDx and Emory laboratories and as likely benign by Illumina Clinical Services. In total this variant is present in 1 individual with ARVC (Bao et al. 2013). According to the test report, "algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The glutamine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies." The codons at neighboring amino acids are also not conserved across species. The variant was reported online in 68 of 141,074 individuals (MAF=0.0241%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 10 of 9,467 individuals of East Asian descent (MAF=0.053%), 14 of 18,232 individuals of Latino descent (MAF=0.038%), 35 of 63,209 individuals of European (non-Finnish) descent (MAF=0.028%), 5 of 15,448 individuals of South Asian descent (MAF=0.016%), 2 of 14,901 individuals of African descent (MAF=0.008%) and 2 of 3,703 individuals of other descent (MAF=0.027%). Note that the phenotype of the individuals in these datasets is not publicly available. The datasets arecomprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease: Absent from 600 Chinese control alleles (Bao et al 2013)

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