rs377715841

Positions:

• chr6-7582775-G-A
• chr6-7582775-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_004415.4(DSP):​c.5513G>A​(p.Arg1838His) variant causes a missense change. The variant allele was found at a frequency of 0.0000626 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 5.59

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26619565).
• BP6: Variant 6-7582775-G-A is Benign according to our data. Variant chr6-7582775-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161225.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.5513G>A	p.Arg1838His	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4184G>A	p.Arg1395His	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.3716G>A	p.Arg1239His	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5513G>A	p.Arg1838His	missense_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3716G>A	p.Arg1239His	missense_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4184G>A	p.Arg1395His	missense_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251362 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2014	The R1838H variant in the DSP gene has been reported in one individual with DCM who also harbored a R907H variant in DSP (Garcia - Pavia P et al., 2011). This individual's parent, who also harbored the R1838H variant, had DCM with fatty infiltrate and fibrosis in the right ventricle. The authors did not report whether the parent harbored R907H. Additionally, R1838H was identified on whole genome sequencing in one individual with a family history of vascular disease and early sudden death (Ashley E et al., 2010). This individual had two other rare variants identified in the TMEM43 and MYPBC3 genes. Furthermore, R1838H was observed in only 3/8600 alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico algorithms are not consistent in their predictions but at least two concur that R1838H is damaging to the protein structure/function. However, R1838H is only a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The R1838 residue is not well conserved across species, and definitive mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2022	Variant summary: DSP c.5513G>A (p.Arg1838His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (7.2e-05 vs 0.0002), allowing no conclusion about variant significance. c.5513G>A has been reported in the literature in individuals affected with DCM, HCM, or unexplained intrauterine fetal death. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n=1, likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with histidine at codon 1838 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28288337), dilated cardiomyopathy (PMID: 21859740), hypertrophic cardiomyopathy (PMID: 30775854), unexplained intrauterine fetal death (PMID: 33762593), and in an individual with a family history of atherosclerotic vascular disease and early sudden death (PMID: 20435227). This variant has also been identified in 20/282730 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 08, 2023

This missense variant replaces arginine with histidine at codon 1838 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28288337), dilated cardiomyopathy (PMID: 21859740), hypertrophic cardiomyopathy (PMID: 30775854), unexplained intrauterine fetal death (PMID: 33762593), and in an individual with a family history of atherosclerotic vascular disease and early sudden death (PMID: 20435227). This variant has also been identified in 20/282730 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2023

The p.R1838H variant (also known as c.5513G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 5513. The arginine at codon 1838 is replaced by histidine, an amino acid with highly similar properties. This variant co-occurred with a second DSP variant in a proband and parent reported to have dilated cardiomyopathy (Garcia-Pavia P et al. Heart. 2011;97:1744-52), and was also detected in an individual reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC) (Chen X et al. Forensic Sci Int. 2017;275:14-22). This variant has also been identified in individuals not known to have ARVC on review of health records (Haggerty CM et al. Genet Med. 2017;11;19(11):1245-1252), and has been detected in an exome cohort (Andreasen C et al. Eur J Hum Genet. 2013;21:918-28). In another study, this variant was detected with other variants in cardiac-related genes in an individual with family history of vascular disease and sudden death (Ashley EA et al. Lancet. 2010;375:1525-35). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Primary dilated cardiomyopathy Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0090	D;T
Polyphen		0.90	P;.
Vest4		0.84
MVP		0.81
MPC		0.58
ClinPred		0.36	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.23

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: rs377715841; hg19: chr6-7583008; COSMIC: COSV65792124;