rs141508330

Positions:

chr6-7579752-T-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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:1

Conservation

PhyloP100: 3.86

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.3562T>C	p.Tyr1188His	missense_variant	23/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.3562T>C	p.Tyr1188His	missense_variant	23/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3562T>C	p.Tyr1188His	missense_variant	23/24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.3562T>C	p.Tyr1188His	missense_variant	23/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.3562T>C	p.Tyr1188His	missense_variant	23/24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.3562T>C	p.Tyr1188His	missense_variant	23/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151814

Hom.:

Cov.:

show subpopulations

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:

AN:

250516

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135430

show subpopulations

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.:

Cov.:

AF XY:

0.000312

AC XY:

227

AN XY:

727076

show subpopulations

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:

AN:

151814

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74104

show subpopulations

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.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2024	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:3

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 08, 2015	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 20, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 24, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.065

MetaRNN

Benign

0.26

T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.7

L;L

PrimateAI

Uncertain

0.74

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over