11-19182719-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003476.5(CSRP3):c.536C>T(p.Thr179Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T179A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CSRP3
NM_003476.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 6.77

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 7 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5 link	c.536C>T	p.Thr179Met	missense_variant	Exon 6 of 6	ENST00000265968.9	NP_003467.1	P50461-1A2TDB8
CSRP3	NM_001369404.1 link	c.367C>T	p.Arg123Trp	missense_variant	Exon 5 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9 link	c.536C>T	p.Thr179Met	missense_variant	Exon 6 of 6	1	NM_003476.5	ENSP00000265968.3		P50461-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152130

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:

0.000480

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251428

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111966

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000506

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 26, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Thr179Met (c.536C>T) in exon 7 of the CSRP3 gene (NM_003476.4) Given the weak case data and presence in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of hypertrophic cardiomyopathy (not including this patient's family). There is no case data. This variant is present in ClinVar. It is classified as a variant of uncertain significance by LMM and likely pathogenic by the Laboratory of Genetics and Molecular Cardiology, University of SÃ£o Paulo - Sarcomeric Human Cardiomyopathy Registry (ShaRe). LMM has seen this variant once in one individual. Per the test report, "algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0")." The threonine at codon 179 is weakly conserved across species. No other variants have been reported in association with disease at this codon or nearby codons. The variant was reported online in 9 of 123,067 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 5 of 7,652 individuals of African descent (MAF=0.033%), 3 of 16,790 individuals of Latino descent and 1 of 2,741 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Apr 09, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CSRP3 c.536C>T; p.Thr179Met variant (rs142019584), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 163007). This variant is found on only eight chromosomes (8/251428 alleles) in the Genome Aggregation Database. The threonine at codon 179 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Thr179Met variant is uncertain at this time. -

Jul 22, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with cardiomyopathy in published literature (Lipari et al., 2020; Burstein et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32746448, 31919335) -

Hypertrophic cardiomyopathy 12

Pathogenic:1

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

CSRP3-related disorder

Uncertain:1

Sep 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CSRP3 c.536C>T variant is predicted to result in the amino acid substitution p.Thr179Met. This variant was reported in individuals with cardiomyopathy (Lipari et al. 2020. PubMed ID: 31919335; Burstein et al. 2020. PubMed ID: 32746448, supplementary data). This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-19204266-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Uncertain:1

Aug 23, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Thr179Met variant in CSRP3 has not been previously reported in individuals w ith cardiomyopathy but has been identified in 1/8586 of European American chromo somes and 1/4398 of African American chromosomes by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS/; dbSNP rs142019584). Computational ana lyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, an d SIFT) do not provide strong support for or against an impact to the protein. A dditional information is needed to fully assess the clinical significance of the Thr179Met variant. The Thr179Met variant in CSRP3 (allele frequency=1/8586 of European American chromosomes and 1/4398 of African American; dbSNP rs142019584) ** -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 179 of the CSRP3 protein (p.Thr179Met). This variant is present in population databases (rs142019584, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 163007). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Cardiovascular phenotype

Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T179M variant (also known as c.536C>T), located in coding exon 5 of the CSRP3 gene, results from a C to T substitution at nucleotide position 536. The threonine at codon 179 is replaced by methionine, an amino acid with similar properties. This variant has been detected in an individual with hypertrophic cardiomyopathy; however, details were limited (Burstein DS et al. Pediatr Res. 2021 May;89(6):1470-1476). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.38

T;T

M_CAP

Uncertain

0.089

MetaRNN

Uncertain

0.43

T;T

PhyloP100

6.8

ClinPred

0.12

GERP RS

6.1

Varity_R

0.22

Mutation Taster

=78/22

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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 for variant 11:19182719 G>A . It may be empty.

11-19182719-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over