NM_004415.4:c.8501G>A

Variant names:

• chr6-7585763-G-A
• rs121912999
• NM_004415.4:c.8501G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004415.4(DSP):​c.8501G>A​(p.Arg2834His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R2834C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.63
• Publications: 25 publications found

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]

DSP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 6-7585763-G-A is Pathogenic according to our data. Variant chr6-7585763-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16847.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.8501G>A	p.Arg2834His	missense_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.7172G>A	p.Arg2391His	missense_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.6704G>A	p.Arg2235His	missense_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8501G>A	p.Arg2834His	missense_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455570 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 723978

African (AFR) AF: 0.00 AC: 0 AN: 33060

American (AMR) AF: 0.00 AC: 0 AN: 43800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108524

Other (OTH) AF: 0.00 AC: 0 AN: 60068

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000262 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Mar 21, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2834His variant in DSP has been reported in 1 individual with ARVC (Yang 2006). It was absent from large population studies. In vivo and in vitro functional studies, including a transgenic mouse model, demonstrate that the presence of this variant results in cardiomyocyte apoptosis, cardiac fibrosis, and cardiac dysfunction, which is consistent with ARVC (Yang 2006, Albrecht 2015, Martherus 2016). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS3, PM2, PP3. -

Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1

Sep 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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 Pathogenic:1

Nov 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2834 of the DSP protein (p.Arg2834His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16917092). ClinVar contains an entry for this variant (Variation ID: 16847). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DSP function (PMID: 25733715, 26545710). 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. -

Cardiomyopathy Uncertain:1

Jan 27, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 2834 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. .A functional study has determined p.Arg2834 to be a methylation site (PMID: 25733715). This p.Arg2834His variant has been shown to block the GSK3 phosphorylation cascade and result in aberrant intermediate filament localization in both cultured keratinocytes (PMID: 25733715) and in the hearts of transgenic mice with cardiac-restricted over-expression of this variant (PMID: 16917092, 26545710). Additionally, the transgenic mice develop increased cardiomyocyte apoptosis, myocardial fibrosis, lipid accumulation, as well as ventricular enlargement and cardiac dysfunction (PMID: 16917092, 26545710). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16917092). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, a few functional studies have indicated that this variant may play a role in disease. However, the available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		6.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.69		Loss of methylation at R2834 (P = 0.0279);.;
MVP		0.91
MPC		0.91
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.59
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912999; hg19: chr6-7585996; COSMIC: COSV60940835; COSMIC: COSV60940835;