rs28931610

Positions:

• chr6-7584358-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5 PP3_Strong PP5

The NM_004415.4(DSP):​c.7096C>T​(p.Arg2366Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R2366H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.78

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 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7584359-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 6-7584358-C-T is Pathogenic according to our data. Variant chr6-7584358-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16841.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.7096C>T	p.Arg2366Cys	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.5767C>T	p.Arg1923Cys	missense_variant	24/24
DSP	NM_001008844.3	c.5299C>T	p.Arg1767Cys	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.7096C>T	p.Arg2366Cys	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.5299C>T	p.Arg1767Cys	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.5767C>T	p.Arg1923Cys	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2366 of the DSP protein (p.Arg2366Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive Carvajal syndrome (PMID: 11841538, 30133754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16841). 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. This variant disrupts the p.Arg2366 amino acid residue in DSP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20738328). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2024

Published functional studies suggest this variant results in impairment of ligand binding, however additional studies are needed to validate the functional effect of this variant (PMID: 30354334); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35008956, 11841538, 21981446, 30133754, 30354334) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 16, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg2366Cy s variant in DSP has been reported in the compound heterozygous state in 1 indiv idual with clinical features of Naxos disease (skin fragility and woolly hair sy ndrome; Whittock 2002), but has not been identified in large population studies. A different amino acid change (p.Arg2366His) at the same codon has been reporte d in the homozygous state in 1 individual with clinical features of Naxos diseas e and segregated with disease in 4 affected family members (Al-Owain 2011). Howe ver, neither family presented with a cardiac phenotype. Computational prediction tools and conservation analysis suggest that the p.Arg2366Cys variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. When inherited in a recessive manner, variants in DSP can result in ARVC or DCM with woolly hair and keratoderma or other skin findings (Norgett 200 0, Alcalai 2003). In summary, while there is some suspicion for a pathogenic rol e, the clinical significance of the p.Arg2366Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.89		Gain of methylation at K2361 (P = 0.0376);.;
MVP		0.90
MPC		0.97
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.86

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: rs28931610; hg19: chr6-7584591;