6-7555789-G-A

Variant names:

• chr6-7555789-G-A
• rs140965835
• NM_004415.4:c.242G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004415.4(DSP):​c.242G>A​(p.Cys81Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,614,108 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:3
• Conservation: PhyloP100: 3.52

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.242G>A	p.Cys81Tyr	missense_variant	Exon 2 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.242G>A	p.Cys81Tyr	missense_variant	Exon 2 of 24		NP_001305963.1
DSP	NM_001008844.3	c.242G>A	p.Cys81Tyr	missense_variant	Exon 2 of 24		NP_001008844.1
DSP	NM_001406591.1	c.242G>A	p.Cys81Tyr	missense_variant	Exon 2 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.242G>A	p.Cys81Tyr	missense_variant	Exon 2 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152274 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251244 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135804

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 213 AN: 1461834 Hom.: 2 Cov.: 32 AF XY: 0.000161 AC XY: 117 AN XY: 727228

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000243 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Apr 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Dec 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DSP c.242G>A (p.Cys81Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1614108 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00014 vs 0.0002), allowing no conclusion about variant significance. c.242G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with a variety of phenotypes such as ARVC, idiopathic ventricular fibrillation (IVF), left ventricular hypertrabeculation (LVHT) or LVNC, conduction disease, referral cohort for genetic testing based on a suspected diagnosis of LQTS, BrS, CPVT, HCM, DCM or ARVC (example, Christensen_2010, Visser_2017, Miszalski-Jamka_2017, Arbustini_2017, Marschall_2019). At-least one individual diagnosed with ARVC carried a causative variant in the PKP2 gene that co-segregated with disease in the family, whereas this variant did not (example, Christensen_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=7, likely benign =3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy Uncertain:2

Apr 21, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 81 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic variant in the PKP2 gene that could explain the observed phenotype (PMID 20864495). This variant has been reported in individuals affected with idiopathic ventricular fibrillation (PMID: 28087426), conduction disease (PMID: 28254189) and left ventricular noncompaction (PMID: 28798025). This variant has been identified in 45/282656 chromosomes (37/128999 non-Finnish European 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. -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:2

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (45 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated region which interacts with plakophilin 1 and junction plakoglobin (UniProt). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Cys81Phe) variant has a VUS entry in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS in individuals with idiopathic ventricular fibrillation, HCM, DCM, LVNC, and left ventricular hypertrabeculation (PMID: 28087426, PMID: 30847666, PMID: 28798025, ClinVar). This variant has been identified in an individual with ARVC who had an additional PKP2 canonical splice variant (PMID: 20864495). This variant has also been identified in control individuals (PMID: 20864495) and has conflicting interpretations of pathogenicity in the LOVD database. (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 -

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Oct 22, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a individual with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, this individual also harbored a canonical splice site variant in the PKP2 gene, which was identified in an affected sibling who did not harbor the p.(C81Y) variant (Christensen et al., 2010); Reported in additional unrelated individuals with idiopathic ventricular fibrillation, conduction disease, left ventricular noncompaction cardiomyopathy (LVNC) and/or left ventricular hypertrabeculation, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and ARVC (Visser et al., 2017; Arbustini et al., 2017; Miszalski-Jamka et al., 2017; van Lint et al., 2019; Marschall et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28798025, 28254189, 31737537, 30847666, 20864495, 28087426) -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 81 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic variant in the PKP2 gene that could explain the observed phenotype (PMID 20864495). This variant has been reported in individuals affected with idiopathic ventricular fibrillation (PMID: 28087426), conduction disease (PMID: 28254189) and left ventricular noncompaction (PMID: 28798025). This variant has been identified in 45/282656 chromosomes (37/128999 non-Finnish European 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. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Lethal acantholytic epidermolysis bullosa Uncertain:1

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Woolly hair-skin fragility syndrome Uncertain:1

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1

Mar 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 28, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.75	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	0.97	T;T
Polyphen		0.99	D;.
Vest4		0.84
MVP		0.82
MPC		1.1
ClinPred		0.070	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140965835; hg19: chr6-7556022;