rs142331975

Positions:

• chr18-31089462-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_024422.6(DSC2):​c.607C>T​(p.Arg203Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,578 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. R203H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.59

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31089461-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.607C>T	p.Arg203Cys	missense_variant	5/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.607C>T	p.Arg203Cys	missense_variant	5/17		NP_004940.1
DSC2	NM_001406506.1	c.178C>T	p.Arg60Cys	missense_variant	5/16		NP_001393435.1
DSC2	NM_001406507.1	c.178C>T	p.Arg60Cys	missense_variant	5/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.607C>T	p.Arg203Cys	missense_variant	5/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.607C>T	p.Arg203Cys	missense_variant	5/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.178C>T	p.Arg60Cys	missense_variant	6/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.178C>T	p.Arg60Cys	missense_variant	5/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251392 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the DSC2 protein (p.Arg203Cys). This variant is present in population databases (rs142331975, gnomAD 0.0009%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21062920, 23514727, 25825460). ClinVar contains an entry for this variant (Variation ID: 72377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DSC2 protein function. Experimental studies have shown that this missense change affects DSC2 function (PMID: 21062920). This variant disrupts the p.Arg203 amino acid residue in DSC2. Other variant(s) that disrupt this residue have been observed in individuals with DSC2-related conditions (PMID: 21636032), which suggests that this may be a clinically significant amino acid residue. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 17, 2020	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Nov 15, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 22, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg203Cys variant in DSC2 has been reported in 1 heterozygous Caucasian individual with A RVC (Gehmlich 2011) and in 1 Japanese individual with ARVC who carried 2 additio nal DSC2 variants (Ohno 2013). Testing of relatives of the proband reported by O hno 2013 detected the Arg203Cys variant in 1 of 2 relatives with a possible diag nosis of ARVC. This variant has been previously identified by our laboratory in two homozygous adults of Middle Eastern descent with ARVC and biventricular DCM, one of whom had additional minimal features of recessive ARVC. The variant was absent from large population studies but it should be noted that these did not s urvey a large enough number of Middle Eastern individuals to rule out that it is common in this population. Cell culture studies do suggest that the variant aff ects protein function (Gehmlich 2011) although these types of studies may not ac curately reflect biological function. Computational predictions also support tha t the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg203Cys variant is unce rtain. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

The c.607C>T (p.R203C) alteration is located in exon 5 (coding exon 5) of the DSC2 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the arginine (R) at amino acid position 203 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.9	D;D;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.91
MutPred		0.94		Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);.;
MVP		0.90
MPC		0.49
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.62
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142331975; hg19: chr18-28669425; COSMIC: COSV51867351;