VCV000217145.55 - ClinVar

NM_000070.3(CAPN3):c.1117T>C (p.Trp373Arg)

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.

(17)

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
Pathogenic(3); Likely pathogenic(9); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000070.3(CAPN3):c.1117T>C (p.Trp373Arg)

Variation ID: 217145 Accession: VCV000217145.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q15.1 15: 42396801 (GRCh38) [ NCBI UCSC ] 15: 42688999 (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	Dec 26, 2017	Oct 20, 2024	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000070.3:c.1117T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000061.1:p.Trp373Arg	missense
NM_024344.2:c.1117T>C	NP_077320.1:p.Trp373Arg	missense
NM_173087.2:c.973T>C	NP_775110.1:p.Trp325Arg	missense
NC_000015.10:g.42396801T>C
NC_000015.9:g.42688999T>C
NG_008660.1:g.53699T>C
LRG_849:g.53699T>C
LRG_849t1:c.1117T>C	LRG_849p1:p.Trp373Arg

... more HGVS ... less HGVS

Protein change

W373R, W325R

Other names

p.(Trp373Arg)

Canonical SPDI

NC_000015.10:42396800:T:C

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA347568 dbSNP: rs775453643 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.
CAPN3		-	-	GRCh38 GRCh37	1736	1878

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.
Autosomal recessive limb-girdle muscular dystrophy type 2A	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Apr 4, 2024	RCV000201159.21
not provided	Conflicting interpretations of pathogenicity (8)	criteria provided, conflicting classifications	May 23, 2022	RCV000710091.26
Abnormality of the musculature	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814104.1
Muscular dystrophy, limb-girdle, autosomal dominant 4	Likely pathogenic (1)	criteria provided, single submitter	Jan 5, 2024	RCV003462345.2

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.
Pathogenic (Jul 28, 2015)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000255647.4 First in ClinVar: Oct 19, 2015 Last updated: Dec 10, 2020	Publications: PubMed (4) PubMed: 16627476‚ 18258189‚ 18337726‚ 22443334 Comment: Not found in the total gnomAD dataset, and the data is high quality. Assessment of experimental evidence suggests this variant results in abnormal protein function. … (more) Not found in the total gnomAD dataset, and the data is high quality. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family. (less)
Likely pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the musculature Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755642.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Likely pathogenic (Jul 04, 2023)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045895.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Elevated circulating creatine kinase concentration (present)
Likely pathogenic (Feb 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003822477.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000645464.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 18337726‚ 30564623‚ 18258189 Comment: This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 373 of the CAPN3 protein … (more) This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 373 of the CAPN3 protein (p.Trp373Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 18337726, 30564623; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217145). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 18258189). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004809356.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely pathogenic (Jan 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy, limb-girdle, autosomal dominant 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213777.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Mar 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004136422.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: CAPN3: PM2, PM3 Number of individuals with the variant: 1
Uncertain significance (Oct 10, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800735.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (2) PubMed: 18258189‚ 22443334
Uncertain significance (Dec 28, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000333339.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 Number of individuals with the variant: 4 Sex: mixed
Likely pathogenic (Oct 29, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450290.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 1
Likely pathogenic (Jul 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581630.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3_MOD, PP1_MOD, PM2_SUP, PM3_SUP, PP3	Number of individuals with the variant: 1 Sex: female
Likely pathogenic (May 23, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002520218.2 First in ClinVar: May 28, 2022 Last updated: Mar 04, 2023	Comment: Individual homozygous for the W373R variant was found to have absent CAPN3 protein on western blot (Duno et al., 2008); Not observed at significant frequency … (more) Individual homozygous for the W373R variant was found to have absent CAPN3 protein on western blot (Duno et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18258189, 16627476, 33281875, 22443334, 18337726, 30564623, 32528171, 27535533, 33726816) (less)
Pathogenic (Feb 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV004014008.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PM2, PP2, PP3, PP5
Likely pathogenic (Mar 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: germline	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV004100670.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: This variant was identified in an homozygous state in a patient with limb-girdle muscular dystrophy Number of individuals with the variant: 1 Age: 40-49 years Sex: female Ethnicity/Population group: African
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740459.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800018.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
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Comment:

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 373 of the CAPN3 protein (p.Trp373Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 18337726, 30564623; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217145). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 18258189). For these reasons, this variant has been classified as Pathogenic.

Comment:

Individual homozygous for the W373R variant was found to have absent CAPN3 protein on western blot (Duno et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18258189, 16627476, 33281875, 22443334, 18337726, 30564623, 32528171, 27535533, 33726816)

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
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.	Nallamilli BRR	Annals of clinical and translational neurology	2018	PMID: 30564623
Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies.	Hauerslev S	BMC musculoskeletal disorders	2012	PMID: 22443334
cDNA analyses of CAPN3 enhance mutation detection and reveal a low prevalence of LGMD2A patients in Denmark.	Duno M	European journal of human genetics : EJHG	2008	PMID: 18337726
The importance of conserved amino acid residues in p94 protease sub-domain IIb and the IS2 region for constitutive autolysis.	Ono Y	FEBS letters	2008	PMID: 18258189
Suppressed disassembly of autolyzing p94/CAPN3 by N2A connectin/titin in a genetic reporter system.	Ono Y	The Journal of biological chemistry	2006	PMID: 16627476
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3	-	-	-	-

Text-mined citations for rs775453643 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000070.3(CAPN3):c.1117T>C (p.Trp373Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs775453643 ...