rs1473818298

Variant names:

• chr6-7584759-GGAATGT-G
• rs1473818298
• NM_004415.4:c.7503_7508delTGAATG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_004415.4(DSP):​c.7503_7508delTGAATG​(p.Cys2501_Glu2502del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004415.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-7584759-GGAATGT-G is Pathogenic according to our data. Variant chr6-7584759-GGAATGT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523707.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.7503_7508delTGAATG	p.Cys2501_Glu2502del	disruptive_inframe_deletion	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6174_6179delTGAATG	p.Cys2058_Glu2059del	disruptive_inframe_deletion	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.5706_5711delTGAATG	p.Cys1902_Glu1903del	disruptive_inframe_deletion	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.7503_7508delTGAATG	p.Cys2501_Glu2502del	disruptive_inframe_deletion	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Jul 24, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 19863551). This variant, c.7503_7508del, results in the deletion of 2 amino acid(s) of the DSP protein (p.Cys2501_Glu2502del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 523707). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Cardiomyopathy Uncertain:1

Sep 17, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a deletion of 2 amino acids from the DSP protein. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.

not provided Uncertain:1

May 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; In-frame deletion of 2 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 32081916, 31402444, 19863551)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=4/196	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1473818298; hg19: chr6-7584992;