chr11-19185023-C-A

Variant names:

• chr11-19185023-C-A
• rs377066670
• NM_003476.5:c.437G>T
• CSRP3 p.Arg146Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP3_Moderate

The NM_003476.5(CSRP3):c.437G>T (p.Arg146Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000547 (AC=8) in the gnomAD database across 1,461,802 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000262. 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.R146H: Uncertain_significance (ClinVar VariationId 163009, 2 stars); p.A90= (synonymous): Uncertain_significance (ClinVar VariationId 1519262, 2 stars)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000262 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

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>T p.Arg146Leu	missense	Exon 5 of 6	Prot: NP_003467.1 UniProt:
	CSRP3 NM_001369404.1		c.268G>T p.Ala90Ser	missense	Exon 4 of 5	Prot: NP_001356333.1 UniProt:

CSRP3 NM_003476.5

MANE Select

HGVSc / HGVSpc.437G>Tp.Arg146Leu

Exon rankExon 5 of 6

missense

Prot: NP_003467.1UniProt: A2TDB8P50461-1

CSRP3 NM_001369404.1

HGVSc / HGVSpc.268G>Tp.Ala90Ser

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>T p.Arg146Leu	missense	Exon 5 of 6	Prot: ENSP00000265968.3 UniProt:
	CSRP3 ENST00000533783.2	TSL:1	c.437G>T p.Arg146Leu	missense	Exon 6 of 7	Prot: ENSP00000431813.1 UniProt:
	CSRP3 ENST00000951070.1		c.446G>T p.Arg149Leu	missense	Exon 5 of 6	Prot: ENSP00000621129.1 UniProt:

CSRP3 ENST00000265968.9

TSL:1MANE Select

HGVSc / HGVSpc.437G>Tp.Arg146Leu

Exon rankExon 5 of 6

missense

Prot: ENSP00000265968.3UniProt: P50461-1

CSRP3 ENST00000533783.2

TSL:1

HGVSc / HGVSpc.437G>Tp.Arg146Leu

Exon rankExon 6 of 7

missense

Prot: ENSP00000431813.1UniProt: P50461-1

CSRP3 ENST00000951070.1

HGVSc / HGVSpc.446G>Tp.Arg149Leu

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 0.00000547	AC:8	Hom:0	AN:1461802	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00000970	1	103066	0.00	0	184050

Showing 1 cohortAllele 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
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.74
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Benign	0.21	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D
Mutation Taster	N/A	8/92	disease causing
PhyloP100	Pathogenic	7.9
popEVE	Benign	-3.4
Varity_R	N/A	0.45
VESM-3B	Benign	-11

Showing 20 of 20 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar