rs149513743

Positions:

• chr6-7583569-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_004415.4(DSP):​c.6307A>G​(p.Lys2103Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 7.57

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 -1 ACMG points.

• BP6: Variant 6-7583569-A-G is Benign according to our data. Variant chr6-7583569-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180336.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.6307A>G	p.Lys2103Glu	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4978A>G	p.Lys1660Glu	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.4510A>G	p.Lys1504Glu	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.6307A>G	p.Lys2103Glu	missense_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.4510A>G	p.Lys1504Glu	missense_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4978A>G	p.Lys1660Glu	missense_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251452 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135908

Gnomad AFR exome AF: 0.0000616

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: 0.0000924

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000300 AC: 438 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 206 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lethal acantholytic epidermolysis bullosa Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with a variety of DSP-related cardiac disorders (MIM#607450, 605676, 615821) and DSP-related skin disorders (MIM#609638, 612908, 607655). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance, which is age dependent for arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0115 - Variants in this gene are known to have variable expressivity for arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 37 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Plectin repeat (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been identified in patients who suffered sudden cardiac arrests and dilated cardiomyopathy. It was also one of three variants identified in a patient with stress-induced cardiomyopathy, although the causative variant was not indicated. Finally, this variant has been classified as a VUS by diagnostic laboratories in ClinVar (PMID: 31378211, 29915098, 28416588, 26606670; ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	May 07, 2021	•The p.Lys2103Glu variant in the DSP gene has been previously reported in 3 unrelated individuals, 1 individual with dilated cardiomyopathy, 1 individual with dilated cardiomyopathy who had a second variant of uncertain significant in this gene, and 1 individual with Noonan syndrome and sudden cardiac arrest (Del Ferro et al., 2017; Gigli et al., 2019; Petrin, Soffer and Daniels 2019). • This variant has been identified in 32/129,176 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Computational tools predict that the p.Lys2103Glu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Lys2103Glu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: none] -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2022	The DSP c.6307A>G; p.Lys2103Glu variant (rs149513743) has been reported two individuals with dilated cardiomyopathy (Dal Ferro 2017, Gigli 2019) and in an individual with sudden cardiac arrest and Noonan syndrome (Petrin 2019). The variant is reported in the ClinVar database (Variation ID: 180336) and is found in the non-Finnish European population with an allele frequency of 0.025% (32/129,176 alleles) in the Genome Aggregation Database. The lysine at codon 2103 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.357). Due to limited information, the clinical significance of the p.Lys2103Glu variant is uncertain at this time. References: Dal Ferro M et al. Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. Heart. 2017 Nov;103(21):1704-1710. PMID: 28416588. Gigli M et al. Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2019 Sep 17;74(11):1480-1490. PMID: 31514951. Petrin Z et al. Sudden cardiac arrest in the field in an 18-year-old male athlete with Noonan syndrome: case presentation and 5-year follow-up. Cardiol Young. 2019 Sep;29(9):1214-1216. PMID: 31378211. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2024	Identified in patients with DCM in published literature; one patient harbored an additional variant in the DSP gene (PMID: 28416588, 31514951); Identified in an individual with SCD and primary myocardial fibrosis (PMID: 29915098); Identified in a patient with a clinical diagnosis of Noonan syndrome with survived cardiac arrest (PMID: 31378211); Published functional study suggests this variant is not predicted to significantly alter protein structure (PMID: 35008956); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31514951, 28416588, 26606670, 29915098, 37937776, 31378211, 35008956) -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Oct 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2023

This missense variant replaces lysine with glutamic acid at codon 2103 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 28416588), in an individual affected with sudden cardiac arrest and Noonan syndrome (PMID: 31378211), and in an individual affected with sudden cardiac death due to primary myocardial fibrosis (Holmstrom 2020, dissertation, University of Oulu). This variant has also been identified in 37/282852 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. -

Woolly hair-skin fragility syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 29, 2014

- -

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

Aug 26, 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 15, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D;T
Sift4G	Benign	0.38	T;T
Polyphen		0.82	P;.
Vest4		0.63
MVP		0.83
MPC		0.97
ClinPred		0.25	T
GERP RS		5.2
Varity_R		0.65
gMVP		0.77

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: rs149513743; hg19: chr6-7583802;