chr11-19185011-C-T

Position:

chr11-19185011-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_003476.5(CSRP3):c.449G>A(p.Cys150Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CSRP3
NM_003476.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 7.91

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 9 ACMG points.

PM1

In a domain LIM zinc-binding 2 (size 51) in uniprot entity CSRP3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_003476.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 11-19185011-C-T is Pathogenic according to our data. Variant chr11-19185011-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219444.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5 linkuse as main transcript	c.449G>A	p.Cys150Tyr	missense_variant	5/6	ENST00000265968.9
CSRP3	NM_001369404.1 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9 linkuse as main transcript	c.449G>A	p.Cys150Tyr	missense_variant	5/6	1	NM_003476.5	P1	P50461-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152262

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:

0.0000119

AC:

AN:

251422

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135880

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727234

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74396

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

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2015	The p.Cys150Tyr variant in CSRP3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/66720 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comput ational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Cys150Tyr varia nt is uncertain. -
Uncertain significance, flagged submission	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 28, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data, the incomplete understanding of the role of this gene and the rarity in unselected samples, we consider this variant a variant of uncertain significance. This variant has been seen in at least two unrelated cases of HCM. There is moderate evidence implicating CSRP3 in HCM. One HCM family was found to have linkage to CSRP3 (Geier 2008). Two missense variants (S46R and C58G) show moderate segregation with HCM (5 and 7 segregations, respectively). The LMM's HCM case series includes CSRP3 sequencing on 64 individuals (Alfares et al 2015). They report 9 variants of uncertain significance and no pathogenic or likely pathogenic variants in that gene. There are very few pathogenic or likely pathogenic variants in ClinVar for CSRP3. McKenna's group reported this specific variant in 2 of 223 unrelated patients with HCM in their British cohort (Lopes et al 2013). The variant is not in ClinVar. In silico analysis predicts the variant to be damaging (SIFT, PolyPhen-2, Align-GVGD). The cysteine at codon 150 is conserved across species, as are neighboring amino acids. The variant was reported online in 1 of 60681 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 22nd, 2015). Specifically, the variant was observed in 1 of 33360 European individuals. 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 14, 2024

- -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 150 of the CSRP3 protein (p.Cys150Tyr). This variant is present in population databases (rs761507504, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23396983, 25351510, 33035702; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219444). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2023

Identified in patients with HCM in published literature (Lopes et al., 2013; Lopes et al., 2015; Salazar-Mendiguchia et al., 2020; Yoneda et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25351510, 34495297, 31919335, 34558151, 23396983, 33035702, 36935760) -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 09, 2023

Variant summary: CSRP3 c.449G>A (p.Cys150Tyr) results in a non-conservative amino acid change located in the zinc finger, LIM-type domain (IPR001781) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251422 control chromosomes (gnomAD). c.449G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy and at least two individuals with Arrhythmia (e.g. Lopes_2013, Salazar-Mendigucha_2020, Tadros_2021, Yoneda_2021). In one study, the variant was identified in a total of 16 individuals affected with HCM and in 12 unaffected family members from 11 different families, suggesting it may have reduced penetrance (Salazar-Mendigucha_2020). Alternatively, in this cohort, the variant was associated with a late onset (mean age at diagnosis of approximately 55 years of age) and therefore several of these unaffected individuals may later manifest the disease. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23396983, 33035702, 33495596, 34495297). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three classified the variant as uncertain significance and three classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2024

The c.449G>A (p.C150Y) alteration is located in exon 5 (coding exon 4) of the CSRP3 gene. This alteration results from a G to A substitution at nucleotide position 449, causing the cysteine (C) at amino acid position 150 to be replaced by a tyrosine (Y). …pathogenic summary statement; however, in the heterozygous state this variant may present with reduced penetrance and variable expressivity. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (4/282834) total alleles studied. The highest observed frequency was 0.003% (4/129144) of European (non-Finnish) alleles. In one study, this variant was detected in 11 probands and 5 affected relatives with hypertrophic cardiomyopathy (HCM) as well as in 12 unaffected individuals, suggesting it may exhibit reduced penetrance (Salazar-Mendiguchía, 2020). This variant has also been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited and cases may overlap (Lopes, 2013). This nucleotide position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Hypertrophic cardiomyopathy 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated LIM domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 13 unrelated individuals with hypertrophic cardiomyopathy (PMIDs: 33035702, 23396983, 25351510, ClinVar). It has also been reported as a VUS in multiple clinical testing laboratories (ClinVar). Age-dependent penetrance has been reported for this variant (PMID: 33035702). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.1

H;H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-11

D;.;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0050

D;.;D

Polyphen

1.0

D;D;D

Vest4

0.97

MutPred

0.89

Gain of catalytic residue at I149 (P = 0.0377);Gain of catalytic residue at I149 (P = 0.0377);Gain of catalytic residue at I149 (P = 0.0377);

MVP

0.99

MPC

0.49

ClinPred

1.0

GERP RS

5.4

Varity_R

0.95

gMVP

0.90

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