11-19192340-A-G

Variant names:

• chr11-19192340-A-G
• rs776468900
• NM_003476.5:c.109T>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.109T>C​(p.Cys37Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,120 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.21

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, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.109T>C	p.Cys37Arg	missense_variant	Exon 2 of 6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.109T>C	p.Cys37Arg	missense_variant	Exon 2 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.109T>C	p.Cys37Arg	missense_variant	Exon 2 of 6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460120 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726520

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Mar 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Has not been previously published as pathogenic or benign to our knowledge -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:1

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 1475134). This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. This variant is present in population databases (rs776468900, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 37 of the CSRP3 protein (p.Cys37Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T;T;.;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;.;.;H;H;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D;.;.;.;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.028	D;.;.;.;D;.
Sift4G	Uncertain	0.032	D;.;.;.;D;.
Polyphen		1.0	D;.;.;D;D;.
Vest4		0.97
MutPred		0.85		Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);
MVP		0.97
MPC		0.49
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.96
gMVP		0.92

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

Other links and lift over

dbSNP: rs776468900; hg19: chr11-19213887;