18-31086694-G-T

Position:

• chr18-31086694-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_024422.6(DSC2):​c.824C>A​(p.Thr275Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T275M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31086694-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.824C>A	p.Thr275Lys	missense_variant	7/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.824C>A	p.Thr275Lys	missense_variant	7/17		NP_004940.1
DSC2	NM_001406506.1	c.395C>A	p.Thr132Lys	missense_variant	7/16		NP_001393435.1
DSC2	NM_001406507.1	c.395C>A	p.Thr132Lys	missense_variant	7/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.824C>A	p.Thr275Lys	missense_variant	7/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.824C>A	p.Thr275Lys	missense_variant	7/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.395C>A	p.Thr132Lys	missense_variant	8/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.395C>A	p.Thr132Lys	missense_variant	7/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Thr275Lys v ariant in DSC2 has been identified by our laboratory in 2 individuals with ARVC from one family who carried a second variant on the other copy of the DSC2 gene. The Thr275Lys variant was also detected in an affected relative and has not bee n identified in large population studies. Of note, another variant at this posit ion, Thr275Met, was reported in 1 individual with ARVC in the homozygous state a nd was demonstrated to impact the maturation and intracellular localization of t he protein (Gehmlich 2011), although these in vitro assays may not accurately re present biological function. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Thr275Lys variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. Although this data supports that the Thr275Lys var iant may be pathogenic, additional studies are needed to fully assess its clinic al significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 03, 2023

This missense variant replaces threonine with lysine at codon 275 of the DSC2 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28588093). This variant has not been identified 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:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2019

Has not been previously reported as pathogenic or benign to our knowledge; A different missense change at this residue (T275M) has been reported in the published literature, as pathogenic in the homozygous state in a patient with ARVC, and the patient's heterozygous children were asymptomatic (Gehmlich et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21062920, 28588093) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

The c.824C>A (p.T275K) alteration is located in exon 7 (coding exon 7) of the DSC2 gene. This alteration results from a C to A substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by a lysine (K). 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	0.89
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.066	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.2	D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.57		Gain of ubiquitination at T275 (P = 0.023);Gain of ubiquitination at T275 (P = 0.023);.;
MVP		0.79
MPC		0.47
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.78

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: rs397517404; hg19: chr18-28666657;