11-19185023-C-T

Variant names:

• chr11-19185023-C-T
• rs377066670
• NM_003476.5:c.437G>A
• CSRP3 p.Arg146His

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO4_SupportingO6_SupportingO7_Supporting

The NM_003476.5(CSRP3):c.437G>A (p.Arg146His) variant causes a missense change involving the alteration of a conserved nucleotide. The gene CSRP3 is a known oncogene (CancerMine: 1 oncogene citations). The variant allele was found at a cumulative frequency of 0.0000242 (AC=39) in the gnomAD database across 1,614,156 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00003. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R146C: Uncertain_significance (ClinVar VariationId 426380, 2 stars); p.R146L: Uncertain_significance (ClinVar VariationId 2167783, 2 stars); p.A90= (synonymous): Uncertain_significance (ClinVar VariationId 1519262, 2 stars) The variant has been observed in cBioPortal in 6 samples across 6 studies and 4 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 7.91
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 12

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1M

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000030 — very rare (O3 supporting [+1])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=6 | studies=6 | cancer types=4 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003476.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CSRP3 NM_003476.5	MANE Select	c.437G>A p.Arg146His	missense	Exon 5 of 6	Prot: NP_003467.1 UniProt:
	CSRP3 NM_001369404.1		c.268G>A p.Ala90Thr	missense	Exon 4 of 5	Prot: NP_001356333.1 UniProt:

CSRP3 NM_003476.5

MANE Select

HGVSc / HGVSpc.437G>Ap.Arg146His

Exon rankExon 5 of 6

missense

Prot: NP_003467.1UniProt: A2TDB8P50461-1

CSRP3 NM_001369404.1

HGVSc / HGVSpc.268G>Ap.Ala90Thr

Exon rankExon 4 of 5

missense

Prot: NP_001356333.1UniProt: A0A3B3ISZ2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CSRP3 ENST00000265968.9	TSL:1MANE Select	c.437G>A p.Arg146His	missense	Exon 5 of 6	Prot: ENSP00000265968.3 UniProt:
	CSRP3 ENST00000533783.2	TSL:1	c.437G>A p.Arg146His	missense	Exon 6 of 7	Prot: ENSP00000431813.1 UniProt:
	CSRP3 ENST00000951070.1		c.446G>A p.Arg149His	missense	Exon 5 of 6	Prot: ENSP00000621129.1 UniProt:

CSRP3 ENST00000265968.9

TSL:1MANE Select

HGVSc / HGVSpc.437G>Ap.Arg146His

Exon rankExon 5 of 6

missense

Prot: ENSP00000265968.3UniProt: P50461-1

CSRP3 ENST00000533783.2

TSL:1

HGVSc / HGVSpc.437G>Ap.Arg146His

Exon rankExon 6 of 7

missense

Prot: ENSP00000431813.1UniProt: P50461-1

CSRP3 ENST00000951070.1

HGVSc / HGVSpc.446G>Ap.Arg149His

Exon rankExon 5 of 6

missense

Prot: ENSP00000621129.1UniProt: A0ACI8UQB6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152236	Cov:33
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:251390	Cov:
GnomAD4 exome	AF: 0.0000239	AC:35	Hom:0	AN:1461802	Cov:31
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152354	Cov:33
TOPMed (Bravo)	AF: 0.0000416	AC:11	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000523	AC:2	Hom:0	AN:38222	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000197	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000770	AC:1	Hom:	AN:12984	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000330	AC:4	Hom:0	AN:122814	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0000900 *	1	11110	0.0000568 *	1	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000354	4	112872	0.0000421	8	190046

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 (3)
-	3	-	not provided (3)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	not specified (1)
-	1	-	Prolonged QT interval (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.77
GPN-Star LLR	N/A	-9.0
GPN-Star score	N/A	9.0
LIST_S2	Benign	0.24	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.87	D
Mutation Taster	N/A	19/81	disease causing
PhyloP100	Pathogenic	7.9
popEVE	Benign	-3.4
Varity_R	N/A	0.37
VESM-3B	Benign	-9.7

Showing 20 of 20 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs377066670;

hg19: chr11-19206570;

COSMIC: COSV56389451;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar