rs141508330

Variant names:

• chr6-7579752-T-C
• rs141508330
• NM_004415.4:c.3562T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004415.4(DSP):​c.3562T>C​(p.Tyr1188His) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16 B:1
• Conservation: PhyloP100: 3.86

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2630654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.3562T>C	p.Tyr1188His	missense_variant	Exon 23 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3562T>C	p.Tyr1188His	missense_variant	Exon 23 of 24		NP_001305963.1
DSP	NM_001008844.3	c.3562T>C	p.Tyr1188His	missense_variant	Exon 23 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3562T>C	p.Tyr1188His	missense_variant	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3562T>C	p.Tyr1188His	missense_variant	Exon 23 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.3562T>C	p.Tyr1188His	missense_variant	Exon 23 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151814 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000758 AC: 19 AN: 250516 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135430

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.000133

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000322 AC: 470 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.000312 AC XY: 227 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.000412

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151814 Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6 AN XY: 74104

Gnomad4 AFR AF: 0.0000484

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: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect: reduced desmosomal gene expression and a prolonged APD compared to wildtype (PMID: 36868229); This variant is associated with the following publications: (PMID: 31983221, 31402444, 30975432, 30847666, 35753512, 23861362, 36868229, 27532257, 34389451, 37589201, 37652022) -

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Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:3

Dec 14, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 08, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

The heterozygous variant in the DSP gene (c.3562T>C; p.Tyr1188His) is considered a variant of uncertain significance. This variant is located in a highly conserved amino acid position (to lizards) and in a moderately conserved nucleotide position. The amino acid change is non-conservative and not in a functional domain. The variant is not published in the literature but it was seen in 8 individuals in the ExAC dataset (out of 120632 alleles interrogated at this position). -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Uncertain:2

Dec 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with histidine at codon 1188 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of DSP protein expression and a prolonged action potential duration (PMID: 36868229). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 36868229) and in four individuals affected with dilated cardiomyopathy (PMID: 27532257, 30975432, 31983221). This variant has also been reported in an individual who experienced sudden cardiac arrest (PMID: 34389451), an individual who experienced sudden infant death syndrome (PMID: 37589201), and in an individual with a suspected unknown cardiomyopathy (PMID: 30847666). This variant has been identified in 22/281874 chromosomes (18/128520 non-Finnish European 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. -

Mar 24, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Dec 11, 2023

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: DSP c.3562T>C (p.Tyr1188His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250516 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (7.6e-05 vs 0.0002), allowing no conclusion about variant significance. c.3562T>C has been reported in the literature in individuals affected with DCM and in a patient with sudden cardiac arrest who also carried other potentially pathogenic variants (Mazzarotto_2020, Asatryan_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27532257, 30975432, 31983221). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Sep 23, 2024

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 tyrosine with histidine at codon 1188 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of DSP protein expression and a prolonged action potential duration (PMID: 36868229). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 36868229) and in four individuals affected with dilated cardiomyopathy (PMID: 27532257, 30975432, 31983221). This variant has also been reported in an individual who experienced sudden cardiac arrest (PMID: 34389451), an individual who experienced sudden infant death syndrome (PMID: 37589201), and in an individual with a suspected unknown cardiomyopathy (PMID: 30847666). This variant has been identified in 22/281874 chromosomes (18/128520 non-Finnish European 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. -

Lethal acantholytic epidermolysis bullosa Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Woolly hair-skin fragility syndrome Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype Uncertain:1

Sep 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1188H variant (also known as c.3562T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 3562. The tyrosine at codon 1188 is replaced by histidine, an amino acid with similar properties. This alteration has also been reported in cardiomyopathy and sudden death cohorts; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Asatryan B et al. Am. J. Cardiol., 2019 06;123:2031-2038; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has been detected in an individual reported to have arrhythmogenic cardiomyopathy (van Kampen SJ et al. Stem Cell Reports. 2023 Mar;18(3):749-764). In vitro studies suggest this variant may impact protein function; however, additional evidence is needed to confirm these findings (van Kampen SJ et al. Stem Cell Reports. 2023 Mar;18(3):749-764). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Oct 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.053	T;T
Sift4G	Benign	0.54	T;T
Polyphen		1.0	D;.
Vest4		0.70
MVP		0.73
MPC		0.94
ClinPred		0.083	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.47

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: rs141508330; hg19: chr6-7579985;