rs104894204

Positions:

• chr11-19188245-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_003476.5(CSRP3):​c.172T>G​(p.Cys58Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,086 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.22

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain LIM zinc-binding 1 (size 51) in uniprot entity CSRP3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003476.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.172T>G	p.Cys58Gly	missense_variant	3/6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.113-1897T>G		intron_variant			NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.172T>G	p.Cys58Gly	missense_variant	3/6	1	NM_003476.5	ENSP00000265968	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726844

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2008

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2019

The p.C58G variant (also known as c.172T>G), located in coding exon 2 of the CSRP3 gene, results from a T to G substitution at nucleotide position 172. The cysteine at codon 58 is replaced by glycine, an amino acid with highly dissimilar properties. This variant has been reported to segregate with hypertrophic cardiomyopathy in a single large German family (Geier C et al. Circulation, 2003 Mar;107:1390-5; Geier C et al. Hum. Mol. Genet., 2008 Sep;17:2753-65). In vitro functional studies suggest C58G disrupts protein function, and mice homozygous for a knock-in C58G allele develop cardiomyopathy and exhibit severely decreased levels of CSRP3 protein; however, heterozygous knock-in mice are unaffected and the physiological relevance of the in vitro results is unclear (Janin A et al. Gene, 2018 Nov;676:110-116; Ehsan M et al. J. Mol. Cell. Cardiol., 2018 Aug;121:287-296). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D;.;D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;T;.;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	H;.;H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-12	D;.;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;.;D;D
Vest4		0.98
MutPred		0.90		Loss of stability (P = 0.0167);Loss of stability (P = 0.0167);Loss of stability (P = 0.0167);Loss of stability (P = 0.0167);
MVP		0.98
MPC		0.38
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104894204; hg19: chr11-19209792;