11-19185022-GC-CA

Variant names:

• chr11-19185022-GC-CA
• NM_003476.5:c.437_438delGCinsTG
• CSRP3 p.Arg146Leu

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 (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_003476.5(CSRP3):c.437_438delGCinsTG (p.Arg146Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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.R146L: Uncertain_significance (ClinVar VariationId 2167783, 2 stars); p.A90= (synonymous): Uncertain_significance (ClinVar VariationId 1519262, 2 stars)

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Uncertain_significance. The variant received 4 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		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 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.437_438delGCinsTG p.Arg146Leu	missense	N/A	Prot: NP_003467.1 UniProt:
	CSRP3 NM_001369404.1		c.268_269delGCinsTG p.Ala90Cys	missense	N/A	Prot: NP_001356333.1 UniProt:

CSRP3 NM_003476.5

MANE Select

HGVSc / HGVSpc.437_438delGCinsTGp.Arg146Leu

Exon rankN/A

missense

Prot: NP_003467.1UniProt: A2TDB8P50461-1

CSRP3 NM_001369404.1

HGVSc / HGVSpc.268_269delGCinsTGp.Ala90Cys

Exon rankN/A

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.437_438delGCinsTG p.Arg146Leu	missense	N/A	Prot: ENSP00000265968.3 UniProt:
	CSRP3 ENST00000533783.2	TSL:1	c.437_438delGCinsTG p.Arg146Leu	missense	N/A	Prot: ENSP00000431813.1 UniProt:
	CSRP3 ENST00000951070.1		c.446_447delGCinsTG p.Arg149Leu	missense	N/A	Prot: ENSP00000621129.1 UniProt:

CSRP3 ENST00000265968.9

TSL:1MANE Select

HGVSc / HGVSpc.437_438delGCinsTGp.Arg146Leu

Exon rankN/A

missense

Prot: ENSP00000265968.3UniProt: P50461-1

CSRP3 ENST00000533783.2

TSL:1

HGVSc / HGVSpc.437_438delGCinsTGp.Arg146Leu

Exon rankN/A

missense

Prot: ENSP00000431813.1UniProt: P50461-1

CSRP3 ENST00000951070.1

HGVSc / HGVSpc.446_447delGCinsTGp.Arg149Leu

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr11-19206569;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar