VCV002940568.2 - ClinVar

NM_003476.5(CSRP3):c.113-3C>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003476.5(CSRP3):c.113-3C>A

Variation ID: 2940568 Accession: VCV002940568.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.1 11: 19188307 (GRCh38) [ NCBI UCSC ] 11: 19209854 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 29, 2024	Nov 24, 2024	Sep 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003476.5:c.113-3C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001369404.1:c.113-1959C>A		intron variant
NM_003476.4:c.113-3C>A
NC_000011.10:g.19188307G>T
NC_000011.9:g.19209854G>T
NG_011932.2:g.27267C>A
LRG_440:g.27267C>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:19188306:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CSRP3		-	-	GRCh38 GRCh37	420	458

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Dilated cardiomyopathy 1M Hypertrophic cardiomyopathy 12	Uncertain significance (1)	criteria provided, single submitter	Apr 3, 2023	RCV003799878.2
Hypertrophic cardiomyopathy 12	Likely pathogenic (1)	criteria provided, single submitter	Sep 20, 2024	RCV004787034.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy 12 Dilated cardiomyopathy 1M Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004587291.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: This sequence change falls in intron 3 of the CSRP3 gene. It does not directly change the encoded amino acid sequence of the CSRP3 protein. … (more) This sequence change falls in intron 3 of the CSRP3 gene. It does not directly change the encoded amino acid sequence of the CSRP3 protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). (less)
Likely pathogenic (Sep 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 12 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398232.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 33035702 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 12 (MIM#612124). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with biallelic variants have a more severe phenotype and/or an earlier onset of symptoms (PMID: 33035702). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. A mini-gene assay has shown that this variant results in exon 3 skipping, which is predicted to result in p.(Met38Serfs*114), and is expected to escape nonsense-mediated decay (personal communication with Victor Chang Cardiac Research Institute). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) (1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is located in the annotated LIM domain. This variant is expected to disrupt both LIM domains in the CSRP3 protein (DECIPHER). (I) 0710 - Another splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change at this position, c.113-3C>T, has been previously reported as a VUS in an individual with hypertrophic cardiomyopathy (personal communication with Blueprint Genetics). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

This sequence change falls in intron 3 of the CSRP3 gene. It does not directly change the encoded amino acid sequence of the CSRP3 protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%).

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 12 (MIM#612124). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with biallelic variants have a more severe phenotype and/or an earlier onset of symptoms (PMID: 33035702). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. A mini-gene assay has shown that this variant results in exon 3 skipping, which is predicted to result in p.(Met38Serfs*114), and is expected to escape nonsense-mediated decay (personal communication with Victor Chang Cardiac Research Institute). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) (1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is located in the annotated LIM domain. This variant is expected to disrupt both LIM domains in the CSRP3 protein (DECIPHER). (I) 0710 - Another splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change at this position, c.113-3C>T, has been previously reported as a VUS in an individual with hypertrophic cardiomyopathy (personal communication with Blueprint Genetics). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals.	Salazar-Mendiguchía J	European journal of medical genetics	2020	PMID: 33035702
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003476.5(CSRP3):c.113-3C>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...