rs397516855

Variant names:

• chr11-19186344-GGGACCTGTT-G
• rs397516855
• NM_003476.5:c.282-5_285delAACAGGTCC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003476.5(CSRP3):​c.282-5_285delAACAGGTCC​(p.Gln94fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSRP3 NM_003476.5 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 3.83
• Publications: 1 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

  Inheritance: AD, SD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• hypertrophic cardiomyopathy 12

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1M

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-19186344-GGGACCTGTT-G is Pathogenic according to our data. Variant chr11-19186344-GGGACCTGTT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44693.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.282-5_285delAACAGGTCC	p.Gln94fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 4 of 6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.113-5_116delAACAGGTCC	p.Ser38fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 3 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.282-5_285delAACAGGTCC	p.Gln94fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 4 of 6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CSRP3 c.282-5_285del variant (rs397516855, ClinVar Variation ID 44693) is reported in the literature in individuals hypertrophic or dilated cardiomyopathy (van Lint 2019, Walsh 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant deletes the canonical splice acceptor site of intron 4 as well as four nucleotides of exon 4, which is likely to negatively impact gene function. Loss of function variants in CSRP3 have been reported in individuals affected with hypertrophic cardiomyopathy, but the inheritance pattern is not clear (Huang 2022, Janin 2018, Lipari 2020, van Rijsingen 2009). Furthermore, the CSRP3 gene is not constrained; therefore, it is unclear if loss of function is an established disease mechanism. Based on available information, the clinical significance of this variant is uncertain at this time. References: Huang H et al. CSRP3, p.Arg122Ter, is responsible for hypertrophic cardiomyopathy in a Chinese family. J Gene Med. 2022 Jan;24(1):e3390. PMID: 34558151. Janin A et al. First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy. Gene. 2018 Nov 15;676:110-116. PMID: 30012424. Lipari M et al. Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy. Pol Arch Intern Med. 2020 Feb 27;130(2):89-99. PMID: 31919335. van Lint FHM et al. Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. Neth Heart J. 2019 Jun;27(6):304-309. PMID: 30847666. van Rijsingen IA et al. Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest double heterozygosity? Neth Heart J. 2009 Dec;17(12):458-63. PMID: 20087448. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Dec 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 44693). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30847666). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 5 (c.282-5_285del) of the CSRP3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CSRP3 are known to be pathogenic (PMID: 12642359, 14567970, 16352453, 20087448, 34558151). -

not specified Uncertain:1

Mar 08, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The 282-5_285de lAACAGGTCC variant (CSRP3) has not been previously reported in the literature or been previously identified by our laboratory. This variant causes a deletion o f the invariant region of the splice consensus sequence and is predicted to caus e altered splicing leading to an abnormal or absent protein. The impact of loss of function variants in CSRP3 in relation to HCM is not well understood. In su mmary, although this variant may be pathogenic, additional studies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=12/188	disease causing

Splicing

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

Other links and lift over

dbSNP: rs397516855; hg19: chr11-19207891;