NM_001130987.2(DYSF):c.2477G>A (p.Arg826Gln) AND Autosomal recessive limb-girdle muscular dystrophy type 2B

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 31, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001271793.2

Allele description [Variation Report for NM_001130987.2(DYSF):c.2477G>A (p.Arg826Gln)]

NM_001130987.2(DYSF):c.2477G>A (p.Arg826Gln)

Gene:

DYSF:dysferlin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p13.2

Genomic location:

Preferred name:

NM_001130987.2(DYSF):c.2477G>A (p.Arg826Gln)

HGVS:

NC_000002.12:g.71564125G>A
NG_008694.1:g.115503G>A
NM_001130455.2:c.2426G>A
NM_001130976.2:c.2381G>A
NM_001130977.2:c.2381G>A
NM_001130978.2:c.2423G>A
NM_001130979.2:c.2516G>A
NM_001130980.2:c.2474G>A
NM_001130981.2:c.2474G>A
NM_001130982.2:c.2519G>A
NM_001130983.2:c.2426G>A
NM_001130984.2:c.2384G>A
NM_001130985.2:c.2477G>A
NM_001130986.2:c.2384G>A
NM_001130987.2:c.2477G>AMANE SELECT
NM_003494.4:c.2423G>A
NP_001123927.1:p.Arg809Gln
NP_001124448.1:p.Arg794Gln
NP_001124449.1:p.Arg794Gln
NP_001124450.1:p.Arg808Gln
NP_001124451.1:p.Arg839Gln
NP_001124452.1:p.Arg825Gln
NP_001124453.1:p.Arg825Gln
NP_001124454.1:p.Arg840Gln
NP_001124455.1:p.Arg809Gln
NP_001124456.1:p.Arg795Gln
NP_001124457.1:p.Arg826Gln
NP_001124458.1:p.Arg795Gln
NP_001124459.1:p.Arg826Gln
NP_003485.1:p.Arg808Gln
LRG_845t1:c.2423G>A
LRG_845t2:c.2477G>A
LRG_845:g.115503G>A
LRG_845p1:p.Arg808Gln
LRG_845p2:p.Arg826Gln
NC_000002.11:g.71791255G>A
NM_001130987.1:c.2477G>A
NM_003494.3:c.2423G>A

Protein change:

R794Q

Links:

dbSNP: rs35297901

NCBI 1000 Genomes Browser:

rs35297901

Molecular consequence:

NM_001130455.2:c.2426G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130976.2:c.2381G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130977.2:c.2381G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130978.2:c.2423G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130979.2:c.2516G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130980.2:c.2474G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130981.2:c.2474G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130982.2:c.2519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130983.2:c.2426G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130984.2:c.2384G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130985.2:c.2477G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130986.2:c.2384G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130987.2:c.2477G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003494.4:c.2423G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2B (LGMDR2)
Synonyms:: MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3; Limb-girdle muscular dystrophy, type 2B; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2
Identifiers:: MONDO: MONDO:0009676; MedGen: C1850889; Orphanet: 268; OMIM: 253601

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001453233	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jan 1, 2020)	germline	clinical testing
SCV002768490	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 31, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30564623, 32528171, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001453233

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jan 1, 2020)

germline

clinical testing

SCV002768490

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 31, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

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

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.

Töpf A, Johnson K, Bates A, Phillips L, Chao KR, England EM, Laricchia KM, Mullen T, Valkanas E, Xu L, Bertoli M, Blain A, Casasús AB, Duff J, Mroczek M, Specht S, Lek M, Ensini M, MacArthur DG; MYO-SEQ consortium, Straub V.

Genet Med. 2020 Sep;22(9):1478-1488. doi: 10.1038/s41436-020-0840-3. Epub 2020 Jun 11.

PubMed [citation]

PMID:: 32528171
PMCID:: PMC7462745

See all PubMed Citations (3)

Details of each submission

From Natera, Inc., SCV001453233.1

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768490.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Miyoshi muscular dystrophy 1 (MIM#254130), muscular dystrophy, limb-girdle, autosomal recessive 2 (MIM#253601) and myopathy, distal, with anterior tibial onset (MIM#606768). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 105 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FerB domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in individuals with proximal muscle weakness or limb girdle muscular dystrophy, either with an unspecified zygosity or as single hits (PMID: 30564623, 32528171). This variant is also consistently classified as a VUS by diagnostic laboratories in ClinVar. (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

#	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: May 16, 2025

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