rs138907450
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_004415.4(DSP):c.3862A>C(p.Lys1288Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1288R) has been classified as Likely benign.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.3862A>C | p.Lys1288Gln | missense_variant | Exon 23 of 24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.3862A>C | p.Lys1288Gln | missense_variant | Exon 23 of 24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.3582+280A>C | intron_variant | Intron 23 of 23 | NP_001008844.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.3862A>C | p.Lys1288Gln | missense_variant | Exon 23 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
| DSP | ENST00000418664.2 | c.3582+280A>C | intron_variant | Intron 23 of 23 | 1 | ENSP00000396591.2 | ||||
| DSP | ENST00000710359.1 | c.3862A>C | p.Lys1288Gln | missense_variant | Exon 23 of 24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes 0.000197 AC: 30AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000271 AC: 68AN: 250916Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135746
GnomAD4 exome AF: 0.000289 AC: 423AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.000304 AC XY: 221AN XY: 727234
GnomAD4 genome 0.000197 AC: 30AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
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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This variant is associated with the following publications: (PMID: 24125834, 28341588, 31402444) -
Cardiomyopathy Uncertain:2
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. -
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Arrhythmogenic right ventricular dysplasia 8 Uncertain:2
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ARVC (MIM#607450) and other DSP-related cardiac disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamine. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is coding in the cardiac specific isoform DSPI but non-coding in DSPII which is the isoform regulating keratinocyte adhesion (PMID: 20524011, PMID: 30382575). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (71 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated central fibrous rod domain (UniProt). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Two different variants in the same codon resulting in changes to arginine and asparagine have both been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS in ClinVar and also in an individual with ARVC (PMID: 24125834) and another individual with primary electric disease (PED). The individual with PED also had a variant in DSG2 (PMID: 28341588). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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. -
not specified Uncertain:1
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). -
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
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. -
Lethal acantholytic epidermolysis bullosa Uncertain:1
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. -
Woolly hair-skin fragility syndrome Uncertain:1
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. -
Long QT syndrome Uncertain:1
Criteria: BS1 -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
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Cardiovascular phenotype Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at