NM_000070.3(CAPN3):c.2093G>A (p.Arg698His) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Sep 10, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000644983.7

Allele description [Variation Report for NM_000070.3(CAPN3):c.2093G>A (p.Arg698His)]

NM_000070.3(CAPN3):c.2093G>A (p.Arg698His)

Gene:

CAPN3:calpain 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_000070.3(CAPN3):c.2093G>A (p.Arg698His)

HGVS:

NC_000015.10:g.42409973G>A
NG_008660.1:g.66871G>A
NM_000070.3:c.2093G>AMANE SELECT
NM_024344.2:c.2075G>A
NM_173087.2:c.1817G>A
NM_173088.2:c.557G>A
NM_173089.2:c.98G>A
NM_173090.2:c.98G>A
NP_000061.1:p.Arg698His
NP_077320.1:p.Arg692His
NP_775110.1:p.Arg606His
NP_775111.1:p.Arg186His
NP_775112.1:p.Arg33His
NP_775113.1:p.Arg33His
LRG_849t1:c.2093G>A
LRG_849:g.66871G>A
LRG_849p1:p.Arg698His
NC_000015.9:g.42702171G>A
NM_000070.2:c.2093G>A

Protein change:

R186H

Links:

dbSNP: rs190793093

NCBI 1000 Genomes Browser:

rs190793093

Molecular consequence:

NM_000070.3:c.2093G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.2075G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.557G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173089.2:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173090.2:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1)
Synonyms:: Limb-girdle muscular dystrophy, type 2A; Limb-girdle muscular dystrophy type 2; Muscular dystrophy, pelvofemoral; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009675; MedGen: C1869123; Orphanet: 267; OMIM: 253600

Recent activity

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interleukin-22 receptor subunit alpha-2 isoform 3 precursor [Homo sapiens]
interleukin-22 receptor subunit alpha-2 isoform 3 precursor [Homo sapiens]
gi|31317243|ref|NP_851827.1|

Protein
Tetrapisispora phaffii CBS 4417 hypothetical protein (TPHA0C02260), partial mRNA
Tetrapisispora phaffii CBS 4417 hypothetical protein (TPHA0C02260), partial mRNA
gi|367000154|ref|XM_003684765.1|

Nucleotide
ectonucleoside triphosphate diphosphohydrolase 1 isoform 5 [Homo sapiens]
ectonucleoside triphosphate diphosphohydrolase 1 isoform 5 [Homo sapiens]
gi|256355127|ref|NP_001157653.1|

Protein
RecName: Full=Protein DDI1 homolog 1
RecName: Full=Protein DDI1 homolog 1
gi|74730631|sp|Q8WTU0.1|DDI1_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000766713	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 10, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25135358, 30564623, 10330340, 15689361, 16411092, 21204801, 28492532
SCV000778587	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 16, 2018)	paternal	research	PubMed (1) [See all records that cite this PMID]
SCV000790334	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 15, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001456369	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M.

Ann Clin Transl Neurol. 2018 Dec;5(12):1574-1587. doi: 10.1002/acn3.649.

PubMed [citation]

PMID:: 30564623
PMCID:: PMC6292381

Calpainopathy-a survey of mutations and polymorphisms.

Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, et al.

Am J Hum Genet. 1999 Jun;64(6):1524-40.

PubMed [citation]

PMID:: 10330340
PMCID:: PMC1377896

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000766713.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 698 of the CAPN3 protein (p.Arg698His). This variant is present in population databases (rs190793093, gnomAD 0.01%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) type 2A (PMID: 25135358, 30564623). ClinVar contains an entry for this variant (Variation ID: 499036). 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. This variant disrupts the p.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330340, 15689361, 16411092, 21204801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000778587.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Counsyl, SCV000790334.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001456369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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