6-7567376-C-A

Variant names:

• chr6-7567376-C-A
• rs780626687
• NM_004415.4:c.1067C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004415.4(DSP):​c.1067C>A​(p.Thr356Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,860 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T356T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8
• Conservation: PhyloP100: 7.90

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 24		NP_001008844.1
DSP	NM_001406591.1	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1067C>A	p.Thr356Lys	missense_variant	Exon 9 of 24			ENSP00000518230.1
DSP	ENST00000682228.1	n.391C>A		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152102 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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251198 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727182

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

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:1 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Mar 28, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 26399581, 34352074, Rawal2021[CaseReport], 25227139, 36768812) -

Aug 09, 2016

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: The c.1067C>A (p.Thr356Lys) in DSP gene is a missense change that involves a conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant of interest is located in the spectrin repeat domain that is known to be involved in cytoskeletal structure. The variant is absent from control dataset of ExAC. This variant has been observed in 1 family with 2 affected siblings presented with dilated cardiomyopathy with severe left ventricular insufficiency, woolly hair and focal palmoplantar keratosis. Both pts carried the variant of interest in compound heterozygosity with maternally inherited c.2131_2132delAG, p.S711Cfs*4. Siblings father (an obligate carrier of the variant of interest, deceased) has suffered from a MI from young age. No functional studies determining the functional impact of this variant have been conducted and published at the time of evaluation. One reputable database/clinical laboratory classified this variant as VUS. Additional clinical and functional data are needed to classify this variant with confidence. Taking together, the variant was classified as VUS-Possibly Pathogenic until more information becomes available. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Dec 13, 2023

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 threonine with lysine at codon 356 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with c.2131_2132delAG in two siblings affected with palmoplantar keratoderma, woolly hair and dilated cardiomyopathy (Carvajal syndrome), and the variant in question was inherited from the father who had myocardial infarction at a young age (PMID 25227139). This variant has been reported in another three individuals affected with DSP-related cardiomyopathy from two different families (PMID: 34352074, 36768812). This variant has also been observed in three asymptomatic individuals with imaging abnormalities involving left ventricle when screened with cardiac magnetic resonance, who were from a family with a history of arrhythmogenic ventricular cardiomyopathy and sudden cardiac death (PMID: 34317553). This variant has been identified in 1/251198 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;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 356 of the DSP protein (p.Thr356Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Carvajal syndrome and/or clinical features of arrhythmogenic cardiomyopathy (PMID: 25227139, 34317553, 34352074, 36768812). 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: 199858). 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. 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

Mar 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with lysine at codon 356 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with c.2131_2132delAG in two siblings affected with palmoplantar keratoderma, woolly hair and dilated cardiomyopathy (Carvajal syndrome), and the variant in question was inherited from the father who had myocardial infarction at a young age (PMID 25227139). This variant has been reported in another three individuals affected with DSP-related cardiomyopathy from two different families (PMID: 34352074, 36768812). This variant has also been observed in three asymptomatic individuals with imaging abnormalities involving left ventricle when screened with cardiac magnetic resonance, who were from a family with a history of arrhythmogenic ventricular cardiomyopathy and sudden cardiac death (PMID: 34317553). This variant has been identified in 1/251198 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. -

Primary dilated cardiomyopathy Uncertain:1

Mar 24, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Keratosis palmoplantaris striata 2 Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. -

Cardiovascular phenotype Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T356K variant (also known as c.1067C>A), located in coding exon 9 of the DSP gene, results from a C to A substitution at nucleotide position 1067. The threonine at codon 356 is replaced by lysine, an amino acid with similar properties. This variant was reported in two compound heterozygous siblings with a maternally inherited DSP splicing variant, dilated cardiomyopathy, woolly or sparse hair, and mild palmoplantar keratosis (Pigors M et al. Acta Derm. Venereol., 2015 Mar;95:337-40). This alteration was also reported in family members of a proband who suffered sudden cardiac death and had features of arrhythmogenic right ventricular cardiomyopathy (ARVC) on autopsy; some of the family members who had genetic testing also carried a missense alteration in JUP (Rawal AS et al. JACC Case Rep, 2021 Mar;3:438-442). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Aug 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.45		Gain of ubiquitination at T356 (P = 0.0238);Gain of ubiquitination at T356 (P = 0.0238);
MVP		0.82
MPC		0.90
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.75

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: rs780626687; hg19: chr6-7567609;