6-7580307-A-G

Variant names:

• chr6-7580307-A-G
• rs200745877
• NM_004415.4:c.4117A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004415.4(DSP):​c.4117A>G​(p.Thr1373Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000843 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1373I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 4.14
• Publications: 9 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.4117A>G	p.Thr1373Ala	missense_variant	Exon 23 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4050+67A>G		intron_variant	Intron 23 of 23		NP_001305963.1
DSP	NM_001008844.3	c.3582+535A>G		intron_variant	Intron 23 of 23		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4117A>G	p.Thr1373Ala	missense_variant	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152220 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000677 AC: 17 AN: 250966 AF XY: 0.0000663

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 FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000869 AC: 127 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111944

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000627 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Aug 29, 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 threonine with alanine at codon 1373 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 two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21397041, 27532257), two individuals with self-reported arrhythmia, and one individual diagnosed with paroxysmal tachycardia (PMID: 21397041), as well as multiple asymptomatic individuals (PMID: 23651034). This variant has also been identified in 17/250966 chromosomes (14/113456 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.

Cardiomyopathy Uncertain:1

Apr 09, 2024

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 alanine at codon 1373 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 two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21397041, 27532257), two individuals with self-reported arrhythmia, and one individual diagnosed with paroxysmal tachycardia (PMID: 21397041), as well as multiple asymptomatic individuals (PMID: 23651034). This variant has also been identified in 17/250966 chromosomes (14/113456 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Woolly hair-skin fragility syndrome Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not provided Uncertain:1

Mar 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with ARVC and arrhythmia (Lahtinen et al., 2011; Lahtinen et al., 2013; Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22227473, 21397041, 27532257, 23651034, 35087879, 31402444)

Cardiovascular phenotype Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1373A variant (also known as c.4117A>G), located in coding exon 23 of the DSP gene, results from an A to G substitution at nucleotide position 4117. The threonine at codon 1373 is replaced by alanine, an amino acid with similar properties. This alteration was initially reported in a Finnish male athlete with ventricular tachycardia and an enlarged right ventricle (Lahtinen AM, Heart Rhythm 2011 Aug; 8(8):1214-21; Lahtinen AM, Ann. Med. 2013 Jun; 45(4):328-35). This alteration has been detected in a cohort referred for arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic testing and in a Finnish cohort of sudden death victims with coronary artery disease; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203; V&auml;h&auml;talo JH et al. Front Cardiovasc Med. 2021 Jan;8:755062). This variant has also been detected in Finnish control alleles, and in several individuals from an exome cohort without know ARVC; however, details were limited (Haggerty CM et al. Genet Med. 2017 11;19(11):1245-1252; V&auml;h&auml;talo JH et al. Front Cardiovasc Med. 2021 Jan;8:755062). This amino acid position is well 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

Sep 04, 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 23, 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	Benign	0.18
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.48
Sift	Benign	0.22	T
Sift4G	Benign	0.50	T
Vest4		0.85
ClinPred		0.11	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.77
Mutation Taster		=69/31	polymorphism

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: rs200745877; hg19: chr6-7580540;