11-19188226-C-T

Position:

chr11-19188226-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003476.5(CSRP3):c.191G>A(p.Arg64His) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,613,492 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. R64C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CSRP3
NM_003476.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.83

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5 linkuse as main transcript	c.191G>A	p.Arg64His	missense_variant	3/6	ENST00000265968.9
CSRP3	NM_001369404.1 linkuse as main transcript	c.113-1878G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9 linkuse as main transcript	c.191G>A	p.Arg64His	missense_variant	3/6	1	NM_003476.5	P1	P50461-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

251272

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461306

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 21, 2012

The Arg64His variant in CSRP3 has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 1/4398 of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/). Computational analyses (biochem ical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional inf ormation is needed to fully assess the clinical significance of the Arg64His var iant. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 11, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a VUS-3B Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine, exon 4. (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition: 0.0000212 (6 het, 0 hom). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Arg64Cys): 0.0000389 (11 het, 0 hom) and p.(Arg64Ser) 0.000004 (1 het, 0 hom).. (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Minor change, high conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. Arg64Leu: VUSx1 in ClinVar. p.(Arg64Cys): VUSx2 in ClinVar. (N) 0804 - Variant is present in the population at a low frequency and has previously been described as variant of uncertain significance: ClinVar x2, LOVD3 x1. Shown as VUS in PMID: 27532257 and PMID: 30847666. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Segregation information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 17, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 44690). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 27532257, 30847666). This variant is present in population databases (rs375014380, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 64 of the CSRP3 protein (p.Arg64His). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2022

Identified in a patient with HCM in published literature (Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35241752, 27532257) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2021

The c.191G>A (p.R64H) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a G to A substitution at nucleotide position 191, causing the arginine (R) at amino acid position 64 to be replaced by a histidine (H). 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

0.71

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.88

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.0

M;.;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;.;.;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

D;.;.;D

Sift4G

Uncertain

0.011

D;.;.;D

Polyphen

0.99

D;.;D;D

Vest4

0.60

MVP

0.95

MPC

0.32

ClinPred

0.95

GERP RS

5.6

Varity_R

0.81

gMVP

0.44

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

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