rs1554108296

Positions:

• chr6-7580542-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004415.4(DSP):​c.4352T>C​(p.Leu1451Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1451V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.70

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.4352T>C	p.Leu1451Pro	missense_variant	23/24	ENST00000379802.8
DSP	NM_001008844.3	c.3582+770T>C		intron_variant
DSP	NM_001319034.2	c.4050+302T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.4352T>C	p.Leu1451Pro	missense_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+770T>C		intron_variant		1		A2
DSP	ENST00000710359.1	c.4050+302T>C		intron_variant				A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sudden unexplained death Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

May 03, 2017

The DSP Leu1451Pro was identified in a sudden death case, with no previous diagnosis and no definitive cause found on post mortem (Bagnall RD, et al., 2016). The variant is absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Based on the limited information available and rarity in the general population, we classify DSP Leu1451Pro as a variant of "uncertain significance". -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 02, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) affected by sudden cardiac death (PMID: 27332903). ClinVar contains an entry for this variant (Variation ID: 519346). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1451 of the DSP protein (p.Leu1451Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

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- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The p.L1451P variant (also known as c.4352T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 4352. The leucine at codon 1451 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and a cardiomyopathy genetic testing cohort; however, clinical details were limited in both cases (Bagnall RD et al. N Engl J Med, 2016 Jun;374:2441-52; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.41		Loss of stability (P = 0.015);
MVP		0.94
MPC		0.98
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.82

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: rs1554108296; hg19: chr6-7580775;