Variant 6-7566380-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4

BP4

Computational evidence support a benign effect (MetaRNN=0.40703735).

BP6

Variant 6-7566380-C-T is Benign according to our data. Variant chr6-7566380-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44982.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=9, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/24		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.943C>T	p.Arg315Cys	missense_variant	8/24			ENSP00000518230.1
DSP	ENST00000682228.1 linkuse as main transcript	n.267C>T		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

17

AN:

152038

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

30

AN:

250466

Hom.:

0

AF XY:

0.000126

AC XY:

17

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000871

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000141

AC:

206

AN:

1459882

Hom.:

0

Cov.:

31

AF XY:

0.000146

AC XY:

106

AN XY:

726370

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000148

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000112

AC:

17

AN:

152154

Hom.:

0

Cov.:

33

AF XY:

0.000148

AC XY:

11

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

0

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000539

AC:

2

ALSPAC

AF:

0.00

AC:

0

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.0000741

AC:

9

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we classify this as a variant of unknown significance (VUS). Mutations in the DSP gene have been reported in at least 7% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). Harvard’s LMM has reported this variant in two patients with dilated cardiomyopathy (DCM) who also carried variants in multiple other cardiomyopathy genes. They classified it as a variant of unknown significance (Pugh et al. 2014, Supplementary Data). This is a non-conservative amino acid change from a positively-charged arginine to a polar, uncharged cysteine capable of forming disulfide bonds. The arginine at codon 315 is not conserved across species (it is an arginine in 6 out of 8 vertebrate species, and a leucine in 2 others). In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. No variants within 10 amino acid residues have been listed in HGMD in association with ARVC (HGMD professional version as of January 17, 2014). The closest is Ser299Arg. In total the variant has been seen in 2 out of ~7500 individuals from population datasets. It was found in 1 Han Chinese individual in 1000 Genomes (1/197 Han Chinese individuals total). It was also seen in 1 Caucasian individual in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of March 27, 2014). The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2019	Variant summary: DSP c.943C>T (p.Arg315Cys) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin repeat (IPR018159) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250466 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 87 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.943C>T has been reported in the literature in individuals affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), dilated cardiomyopathy and Brugada syndrome (Bhonsale_2015, Chen_2018, Walsh_2017, Zhao_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with pathogenic variants in VCL (c.1639C>T, p.Arg547) and SCN5A (c.3823G>A, p.Asp1275Asn) genes have been reported in two patients affected with dilated cardiomyopathy and Brugada syndrome, respectively (Pugh_2014, Zhang_2016). Additionally, a co-occurrence with a pathogenic DSP variant (c.6478C>T, p.Arg2160) has been reported in an ARVD/C patient (Bhonsale_2015), providing supporting evidence for a benign role. Results from two recent abstracts presented in scientific conferences from the same group describe the variant to effect DSP binding to CSN6 protein, cardiac CSN6 reduction and early electrical defects found in ARVC in DSP R315C knock-in mice (Liang_2019, Sheikh_2018). The authors highlight the importance of CSN6 at the cardiac desmosome and suggest loss of CSN6 as a new underlying mechanism driving ARVC and sudden death. However, since the role of CSN6 in the cause of ARVC has not been conclusively determined at the time of this classification and these results are not provided in a peer-reviewed, full-text publication, no conclusive interpretations can be drawn. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2019	The p.Arg315Cys variant in DSP (ClinVar variation ID #24440) has been reported in 4 individuals with ARVC, two of whom carried an additional variant sufficient to explain their phenotype (1 in DSP and 1 in PKP2), and in 1 individual with left ventricular dilation (Bhonsale 2015, Ermakov 2014, Walsh 2017, LMM data). This variant was also identified in 3 individuals with childhood onset DCM from two families (LMM data). Two of these (from one family) also carried a pathogenic DSP loss of function variant and had a more severe course of disease than other family members who had only the loss of function variant, suggesting that the p.Arg315Cys variant may have added to disease severity. In addition, this variant has been reported in 2 individuals with Brugada syndrome, one of whom also carried a pathogenic variant in SCN5A (Zhang 2016, Zhao 2016). This variant has been identified in 0.08% (16/19928) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is higher than the maximum expected allele frequency for a pathogenic variant causing autosomal dominant ARVC although it remains compatible with autosomal recessive inheritance, which has been described for DSP. Computational prediction tools and conservation analysis suggest that the Arg315Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Arg315Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3, BS1_Supporting. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 24, 2023	This missense variant replaces arginine with cysteine at codon 315 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts the DSP and CSN6 interaction in vitro and cardiomyocyte-specific DSP knockout mice exhibit baseline electrical defects associated with arrhythmogenic right ventricular cardiomyopathy as well as a significant increase in catecholamine induced arrhythmias when compared with wild-type controls (PMID: 33857019 ). This variant has been reported in individuals affected with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and Brugada syndrome (PMID: 24503780, 25196244, 25616645, 26585738, 27532257, 31983221, 32516855). Three of these individuals also carried pathogenic variants in different genes suggesting that this variant may not have been the cause of disease observed in the affected individuals (PMID: 2450378, 25616645, 25196244). This variant occurs at an appreciable frequency in the general population and has been identified in 35/281858 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. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26585738, 25196244, 25616645, 27532257, 27707468, no PMID, 25820315, 24503780, 30847666, 32516855) -

Lethal acantholytic epidermolysis bullosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Woolly hair-skin fragility syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.943C>T (p.R315C) alteration is located in exon 8 (coding exon 8) of the DSP gene. This alteration results from a C to T substitution at nucleotide position 943, causing the arginine (R) at amino acid position 315 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.022

T

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

33

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.18

D

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.28

T

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.71

T

PROVEAN

Benign

-0.78

N;N

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.93

MVP

0.79

MPC

0.96

ClinPred

0.29

T

GERP RS

5.4

Varity_R

0.50

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

6-7566380-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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