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

gnomAD frequency: 0.00014  dbSNP: rs138907450

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154713	SCV000204393	uncertain significance	not specified	2020-07-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Lys1288Gln variant in DSP has been identified in 10 of 19942 East Asian alleles in gnomAD (0.05%). 2 of 3 computational predictors predict that the variant is damaging. The residue is well conserved, but the variant amino acid is in two mammals (shrew and Tibetan anteloupe). It has been reported in ClinVar with conflicting interpretations (1 likely benign and 9 uncertain significance). It has been identified in 1 individual with ARVC (Bao 2013 PMID: 24125834), 1 infant with HCM (LMM Data), and one individual with primary electrical disease (Proost 2017 PMID: 28341588). This individual also harbored a variant in DSG2. The variant was also identified in another individual with HCM, but this individual harbored an exon 27 deletion in MYBPC3 (Mates 2018 PMID: 29511324).
GeneDx	RCV000723628	SCV000233611	likely benign	not provided	2020-02-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24125834, 28341588, 31402444)
Eurofins Ntd Llc (ga)	RCV000723628	SCV000331395	uncertain significance	not provided	2015-08-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000403440	SCV000465006	uncertain significance	Woolly hair-skin fragility syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000342008	SCV000465008	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000404310	SCV000465009	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000459782	SCV000543227	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620854	SCV000735974	likely benign	Cardiovascular phenotype	2021-09-22	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.
Color Diagnostics, LLC DBA Color Health	RCV000771831	SCV000904544	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 1288 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834) and in an individual affected with cardiac arrhythmia (PMID: 28341588). This variant has also been identified in 71/282292 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771831	SCV002043292	uncertain significance	Cardiomyopathy	2020-08-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000723628	SCV003829145	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318357	SCV004021993	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1
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)