6-7571546-T-G

Position:

• chr6-7571546-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The ENST00000379802.8(DSP):​c.1865T>G​(p.Leu622Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L622P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP ENST00000379802.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.67

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000379802.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7571546-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 372127.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1865T>G	p.Leu622Arg	missense_variant	14/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1865T>G	p.Leu622Arg	missense_variant	14/24		NP_001305963.1
DSP	NM_001008844.3	c.1865T>G	p.Leu622Arg	missense_variant	14/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1865T>G	p.Leu622Arg	missense_variant	14/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.1865T>G	p.Leu622Arg	missense_variant	14/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.1865T>G	p.Leu622Arg	missense_variant	14/24			ENSP00000518230	A2
DSP	ENST00000684395.1	n.249T>G		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2016

The p.L622R variant (also known as c.1865T>G), located in coding exon 14 of the DSP gene, results from a T to G substitution at nucleotide position 1865. The leucine at codon 622 is replaced by arginine, an amino acid with dissimilar properties. An alternate substitution at this position p.L622P (c.1865T>C) has been reported as de novo in one individual with Carvajal syndrome and another individual with erythrokeratodermia-cardiomyopathy (EKC) syndrome, both of whom also showed symptoms of dilated cardiomyopathy; however, proline has been identified as a strong alpha-helix breaker and is more likely to disrupt the conserved helical structure of spectrin repeat 6 than the current arginine substitution (Bitar F et al. J Eur Acad Dermatol Venereol, 2016 Dec;30:e217-e219; Boyden LM et al. Hum. Mol. Genet., 2016 Jan;25:348-57). This amino acid position is highly 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.66		Gain of disorder (P = 0.025);Gain of disorder (P = 0.025);
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.91

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: rs1554107098; hg19: chr6-7571779;