rs121912999

Positions:

• chr6-7585763-G-A
• chr6-7585763-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2834C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.63

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7585762-C-T is described in Lovd as [Likely_pathogenic].
• 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 [Likely_pathogenic]. Clinvar id is 16847.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7585763-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8501G>A	p.Arg2834His	missense_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.6704G>A	p.Arg2235His	missense_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.7172G>A	p.Arg2391His	missense_variant	24/24			ENSP00000518230	A2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2019

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2006

- -

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;.
MutationTaster	Benign	1.0	A;A
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

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