chr6-7581151-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004415.4(DSP):c.4961T>C(p.Leu1654Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,956 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 6.21

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.4961T>C	p.Leu1654Pro	missense_variant	Exon 23 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.4050+911T>C		intron_variant	Intron 23 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3582+1379T>C		intron_variant	Intron 23 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.4961T>C	p.Leu1654Pro	missense_variant	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.3582+1379T>C		intron_variant	Intron 23 of 23	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.4050+911T>C		intron_variant	Intron 23 of 23			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

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:

0.0000319

AC:

AN:

250726

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135694

show subpopulations

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:

0.0000529

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727218

show subpopulations

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

show subpopulations

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

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jul 24, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31402444, 21723241, 26138720, 24070718, 20152563, 20129281, 20524011) -

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Apr 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu1654Pro variant has been previously reported in at least 2 adults with ARVC (Bauce 2010, Xu 2010, Bauce 2011, Rigato 2013 - note that some of these stu dies had overlapping cohorts). In one family (Bauce 2010), the proband carried 2 additional PKP2 variants (one of them being a nonsense variant). Family studies were inconclusive but it is worth noting that the DSP Leu1654Pro variant was in herited from the affected father while the PKP2 nonsense variant was inherited f rom the unaffected mother. This variant has also been identified in 1 homozygous individual (2/119956 alleles) by the Exome Aggregation Consortium (http://exac. broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu1654Pro variant is uncertain. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Uncertain:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Uncertain:1

Feb 19, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 1654 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy but it did not segregate with disease in the family (PMID: 20129281). This variant has also been reported in an individual affected with left ventricular non-compaction cardiomyopathy (PMID: 31568572). This variant has been identified in 8/250726 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. -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Jul 03, 2019

Klaassen Lab, Charite University Medicine Berlin

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype

Uncertain:1

Dec 21, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1654P variant (also known as c.4961T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 4961. The leucine at codon 1654 is replaced by proline, an amino acid with similar properties. This variant co-occurred with additional alterations in the PKP2 gene in a family reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC); however, p.L1654P was not seen in isolation, complicating interpretation of the segregation data (Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42). This variant has also been detected in an individual from a pediatric cardiomyopathy cohort who was reported to have left ventricular non-compaction cardiomyopathy; however, details were limited (Kühnisch J et al. Clin. Genet., 2019 Dec;96:549-559), and in an exome sequencing cohort in an individual not know to have cardiomyopathy (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). 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. -

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

Benign:1

Oct 16, 2024

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

0.93

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Benign

0.064

Eigen_PC

Benign

0.087

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.51

Sift

Uncertain

0.0050

Sift4G

Benign

0.079

Polyphen

0.88

Vest4

0.76

MutPred

0.77

Loss of stability (P = 0.0238);

MVP

0.99

MPC

0.77

ClinPred

0.22

GERP RS

4.8

Varity_R

0.49

gMVP

0.80

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