ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.2120A>G (p.Asp707Gly)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000070.3(CAPN3):c.2120A>G (p.Asp707Gly)
Variation ID: 468648 Accession: VCV000468648.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q15.1 15: 42410432 (GRCh38) [ NCBI UCSC ] 15: 42702630 (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 8, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000070.3:c.2120A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Asp707Gly missense NM_024344.2:c.2102A>G NP_077320.1:p.Asp701Gly missense NM_173087.2:c.1844A>G NP_775110.1:p.Asp615Gly missense NM_173088.2:c.584A>G NP_775111.1:p.Asp195Gly missense NM_173089.2:c.125A>G NP_775112.1:p.Asp42Gly missense NM_173090.2:c.125A>G NP_775113.1:p.Asp42Gly missense NC_000015.10:g.42410432A>G NC_000015.9:g.42702630A>G NG_008660.1:g.67330A>G LRG_849:g.67330A>G LRG_849t1:c.2120A>G LRG_849p1:p.Asp707Gly - Protein change
- D707G, D195G, D42G, D615G, D701G
- Other names
- -
- Canonical SPDI
- NC_000015.10:42410431:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00020 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00015
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00017
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00020
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 | ||
---|---|---|---|---|---|---|
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 |
1729 | 1871 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000542626.19 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2022 | RCV000723534.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 26, 2024 | RCV003476296.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 16, 2021 | RCV002476173.1 | |
Pathogenic (1) |
no assertion criteria provided
|
Feb 2, 2024 | RCV004538015.2 |
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
(Oct 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700548.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Likely pathogenic
(Oct 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: yes
Allele origin:
unknown
|
NeuroMeGen, Hospital Clinico Santiago de Compostela
Accession: SCV000882607.1
First in ClinVar: Feb 04, 2019 Last updated: Feb 04, 2019 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163397.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
Pathogenic
(Jan 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194156.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000070.2(CAPN3):c.2120A>G(D707G) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 25079074, 26632398, 11525884 and 27066573. Classification of … (more)
NM_000070.2(CAPN3):c.2120A>G(D707G) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 25079074, 26632398, 11525884 and 27066573. Classification of NM_000070.2(CAPN3):c.2120A>G(D707G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
Pathogenic
(Dec 01, 2020)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: yes
Allele origin:
inherited
|
Medical Genetic Department, The Affiliated Hospital of Qingdao University
Accession: SCV001468297.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
Comment:
The missense variant c.2120A>G/p.(Asp707Gly) in exon 20 resulted in a single-nucleotide polymorphism (A to G) at site 2120 in the coding region of CAPN3 (NM_000070.2), … (more)
The missense variant c.2120A>G/p.(Asp707Gly) in exon 20 resulted in a single-nucleotide polymorphism (A to G) at site 2120 in the coding region of CAPN3 (NM_000070.2), which introduced an aspartic acid residue that replaced a glycine in codon 707 (Fig. 3A). This variant was previously reported in multiple (>10) homozygous or compound heterozygous patients with LGMDs (PM3-PVS), which co-segregated within a family (PP1-PM). The normal population database includes this variant; its frequency is 0.0148% (42/282854, gnomAD) (PM2); bioinformatics analysis software SIFT, PolyPhen2, and Variant Taster consistently predicted the variant to be harmful (PP3). In addition, the variant is included in ClinVar as a “pathogenic/suspected pathogenic variant.†According to available evidence, the variant is defined as pathogenic (PM3-PVS+PM2+PP1-PM+PP3) based on the 2015 ACMG guidelines for sequence variant interpretation.The WES of this patient revealed compound heterozygous variants in CAPN3, c.2120A>G/p. (Asp707Gly) in exon 20 and c.2201_2202delAT/p.(Tyr734*) in exon 21, which were inherited from his parents and absent from 200 control individuals of similar ethnic origin, indicating that these variants are the pathogenic triggers of the LGMDR1 phenotype. In summary, we observed a sporadic male case of LGMDR1 and identified two compound heterozygous variants in CAPN3, namely c.2120A>G/p. (Asp707Gly) and c.2201_2202delAT/ p.(Tyr734*)), which co-segregated with the LGMDR1 phenotypes in the proband’s family. (less)
Clinical Features:
hyperCKemia (present)
Age: 20-29 years
Sex: male
Ethnicity/Population group: Han population
Geographic origin: China
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002059128.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000468648, PS1_S). The variant … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000468648, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 26632398, PM3_S). A different missense change at the same codon has been reported to be associated with CAPN3 related disorder (ClinVar ID: VCV000290334, PM5_P).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.862, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000148, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Scapular winging (present)
|
|
Pathogenic
(Nov 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Muscular dystrophy, limb-girdle, autosomal dominant 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002790399.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Feb 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018087.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000645487.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 707 of the CAPN3 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 707 of the CAPN3 protein (p.Asp707Gly). This variant is present in population databases (rs200379491, gnomAD 0.2%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10567047, 11525884, 25252031, 26632398). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 468648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy, limb-girdle, autosomal dominant 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211502.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Jan 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201650.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate no detectable protein in the muscle tissue of a patient homozygous for this variant (PMID: 10567047); In silico analysis supports that … (more)
Published functional studies demonstrate no detectable protein in the muscle tissue of a patient homozygous for this variant (PMID: 10567047); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36066420, 25525159, 27363342, 30127231, 30919934, 10567047, 26632398, 31656265, 33899113, 25252031, 25079074, 32573981, 27066573, 34323405, 11525884, 27500519, 32994280, 35314707, 28403181) (less)
|
|
Pathogenic
(May 26, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085554.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
Pathogenic
(Feb 02, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CAPN3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004118657.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The CAPN3 c.2120A>G variant is predicted to result in the amino acid substitution p.Asp707Gly. This variant has been reported with a second CAPN3 variant or … (more)
The CAPN3 c.2120A>G variant is predicted to result in the amino acid substitution p.Asp707Gly. This variant has been reported with a second CAPN3 variant or in the homozygous state in individuals with limb-girdle muscular dystrophy (see, for example, Minami et al. 1999. PubMed ID: 10567047; Chae et al. 2001. PubMed ID: 11525884; Park et al. 2016. PubMed ID: 26632398). This variant is reported in 0.21% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
click to load more click to collapse |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. | Ten Dam L | Clinical genetics | 2019 | PMID: 30919934 |
Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders. | Park HJ | Clinical genetics | 2017 | PMID: 27363342 |
Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations. | Park HJ | Yonsei medical journal | 2016 | PMID: 26632398 |
Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing. | Izumi R | Neurology. Genetics | 2015 | PMID: 27066573 |
Muscle-specific calpain-3 is phosphorylated in its unique insertion region for enrichment in a myofibril fraction. | Ojima K | Genes to cells : devoted to molecular & cellular mechanisms | 2014 | PMID: 25252031 |
Redox state and mitochondrial respiratory chain function in skeletal muscle of LGMD2A patients. | Nilsson MI | PloS one | 2014 | PMID: 25079074 |
Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy. | Chae J | Neuromuscular disorders : NMD | 2001 | PMID: 11525884 |
Mutations of calpain 3 gene in patients with sporadic limb-girdle muscular dystrophy in Japan. | Minami N | Journal of the neurological sciences | 1999 | PMID: 10567047 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 | - | - | - | - |
Text-mined citations for rs200379491 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.