rs121912992

Variant names:

• chr6-7565478-C-A
• rs121912992
• NM_004415.4:c.897C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7565478-C-A
• chr6-7565478-C-G
• chr6-7565478-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004415.4(DSP):​c.897C>A​(p.Ser299Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S299G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.454
• Publications: 1 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: Pathogenic. The variant received 16 ACMG points.

• PS1: Transcript NM_004415.4 (DSP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 6-7565478-C-A is Pathogenic according to our data. Variant chr6-7565478-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2954090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24		NP_001305963.1
DSP	NM_001008844.3	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24		NP_001008844.1
DSP	NM_001406591.1	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 299 of the DSP protein (p.Ser299Arg). 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: 12373648). It has also been observed to segregate with disease in related individuals. 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Apr 17, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S299R variant (also known as c.897C>A), located in coding exon 7 of the DSP gene, results from a C to A substitution at nucleotide position 897. The serine at codon 299 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with DSP-related cardiomyopathy (Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42) and segregated with disease in at least one family (Rampazzo A et al. Am J Hum Genet, 2002 Nov;71:1200-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		-0.45
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.045	D;T
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.81		Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);
MVP		0.99
MPC		0.87
ClinPred		0.99	D
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.90
Mutation Taster		=27/73	disease causing

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: rs121912992; hg19: chr6-7565711;