rs137852764

Positions:

chr11-19188211-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The ENST00000265968.9(CSRP3):c.206A>G(p.Lys69Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,678 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

CSRP3
ENST00000265968.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 7.93

Variant links:

Genes affected

CSRP3 (HGNC:2472): (cysteine and glycine rich protein 3) This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

CSRP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a mutagenesis_site Increases PKC/PRKCA activity. (size 0) in uniprot entity CSRP3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSRP3	NM_003476.5 linkuse as main transcript	c.206A>G	p.Lys69Arg	missense_variant	3/6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1 linkuse as main transcript	c.113-1863A>G		intron_variant			NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9 linkuse as main transcript	c.206A>G	p.Lys69Arg	missense_variant	3/6	1	NM_003476.5	ENSP00000265968	P1	P50461-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251312

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135820

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2022	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 69 of the CSRP3 protein (p.Lys69Arg). This variant is present in population databases (rs137852764, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy with endocardial fibroelastosis (PMID: 8994428, 14567970, 28790153). ClinVar contains an entry for this variant (Variation ID: 8780). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Experimental studies have shown that this missense change affects CSRP3 function (PMID: 14567970, 18250163, 27353086). 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	Fulgent Genetics, Fulgent Genetics	Oct 09, 2021	- -

Dilated cardiomyopathy 1M

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2003

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2024

Initially reported in two deceased infant siblings diagnosed with DCM associated with endocardial fibroelastosis; the variant was also identified in their unaffected mother (PMID: 14567970); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro studies demonstrated that the K69R variant abolishes the interaction between MLP and alpha-actinin-2 and also demonstrated differential localization in the cell as compared with wild-type protein (PMID: 14567970); however, additional studies are needed to validate the functional effect of this variant in vivo; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 8780; ClinVar); This variant is associated with the following publications: (PMID: 22337857, 27896284, 23299917, 28790153, 14567970, 35626289) -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Dec 06, 2019

The CSRP3 Lys69Arg variant has been previously reported in 2 unrelated DCM cases (Zimmerman RS, et al., 2010; Mohaptra B, et al., 2003). In the case reported by Mohaptra B, et al. (2003) 2 siblings died (both around 2 years of age) from DCM no family history of disease was reported. The variant is present in the Exome Aggregation Consortium dataset (MAF=0.0000165; http://exac.broadinstitute.org/). We identified the CSRP3 Lys69Arg in a HCM proband with no family history of disease or sudden cardiac death. A second variant (MYBPC3 Ser871fs) classified as "pathogenic" has also been identified in this proband. Computational tool SIFT and and MutationTaster predict this variant to be "deleterious" and "disease causing", however PolyPhen-2 predicts this variant to be "benign". In summary, based on current literature, rarity in general populations, and our limited familial data we classify CSRP3 Lys69Arg as variant of "uncertain significance". -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The p.K69R variant (also known as c.206A>G), located in coding exon 2 of the CSRP3 gene, results from an A to G substitution at nucleotide position 206. The lysine at codon 69 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in a proband with dilated cardiomyopathy and endocardiofibroelastosis; however, it was also present in the phenotypically normal mother. In vitro analysis suggested that the mutant protein had an altered cellular localization and failed to bind α-actinin-2 (Mohapatra B et al. Mol. Genet. Metab.;80:207-15). In addition, this alteration was reported to enhance PKCα phosphorylation in vitro (Lange S et al. Nat Commun, 2016 Jun;7:12120). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;D;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;.;D

M_CAP

Uncertain

0.098

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.7

M;.;M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

D;.;.;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

D;.;.;D

Sift4G

Uncertain

0.060

T;.;.;T

Polyphen

0.96

P;.;P;P

Vest4

0.86

MVP

0.94

MPC

0.057

ClinPred

0.70

GERP RS

5.6

Varity_R

0.58

gMVP

0.45

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over