6-7571546-T-G

Variant names:

• chr6-7571546-T-G
• rs1554107098
• NM_004415.4:c.1865T>G

Variant summary

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

The NM_004415.4(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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 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 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, 0.895

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1865T>G	p.Leu622Arg	missense_variant	Exon 14 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1865T>G	p.Leu622Arg	missense_variant	Exon 14 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1865T>G	p.Leu622Arg	missense_variant	Exon 14 of 24			ENSP00000518230.1
DSP	ENST00000684395.1	n.249T>G		non_coding_transcript_exon_variant	Exon 2 of 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

Dec 15, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;