NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln) AND Qualitative or quantitative defects of dysferlin

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 7, 2023
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:: RCV000555598.19

Allele description [Variation Report for NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)]

NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)

Gene:

DYSF:dysferlin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p13.2

Genomic location:

Preferred name:

NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)

Other names:

NM_001130455.1(DYSF):c.3116G>A(p.Arg1039Gln); NM_001130976.1(DYSF):c.3071G>A(p.Arg1024Gln); NM_001130977.1(DYSF):c.3071G>A(p.Arg1024Gln); NM_001130978.1(DYSF):c.3113G>A(p.Arg1038Gln); NM_001130979.1(DYSF):c.3206G>A(p.Arg1069Gln); NM_001130980.1(DYSF):c.3164G>A(p.Arg1055Gln); NM_001130981.1(DYSF):c.3164G>A(p.Arg1055Gln); NM_001130982.1(DYSF):c.3209G>A(p.Arg1070Gln); NM_001130983.1(DYSF):c.3116G>A(p.Arg1039Gln); NM_001130984.1(DYSF):c.3074G>A(p.Arg1025Gln); NM_001130985.1(DYSF):c.3167G>A(p.Arg1056Gln); NM_001130986.1(DYSF):c.3074G>A(p.Arg1025Gln); NM_001130987.1(DYSF):c.3167G>A(p.Arg1056Gln); NM_003494.3(DYSF):c.3113G>A(p.Arg1038Gln)

HGVS:

NC_000002.12:g.71570680G>A
NG_008694.1:g.122058G>A
NM_001130455.2:c.3116G>A
NM_001130976.2:c.3071G>A
NM_001130977.2:c.3071G>A
NM_001130978.2:c.3113G>A
NM_001130979.2:c.3206G>A
NM_001130980.2:c.3164G>A
NM_001130981.2:c.3164G>A
NM_001130982.2:c.3209G>A
NM_001130983.2:c.3116G>A
NM_001130984.2:c.3074G>A
NM_001130985.2:c.3167G>A
NM_001130986.2:c.3074G>A
NM_001130987.2:c.3167G>AMANE SELECT
NM_003494.4:c.3113G>A
NP_001123927.1:p.Arg1039Gln
NP_001124448.1:p.Arg1024Gln
NP_001124449.1:p.Arg1024Gln
NP_001124450.1:p.Arg1038Gln
NP_001124451.1:p.Arg1069Gln
NP_001124452.1:p.Arg1055Gln
NP_001124453.1:p.Arg1055Gln
NP_001124454.1:p.Arg1070Gln
NP_001124455.1:p.Arg1039Gln
NP_001124456.1:p.Arg1025Gln
NP_001124457.1:p.Arg1056Gln
NP_001124458.1:p.Arg1025Gln
NP_001124459.1:p.Arg1056Gln
NP_003485.1:p.Arg1038Gln
LRG_845t1:c.3113G>A
LRG_845t2:c.3167G>A
LRG_845:g.122058G>A
LRG_845p1:p.Arg1038Gln
LRG_845p2:p.Arg1056Gln
NC_000002.11:g.71797810G>A
NM_001130987.1:c.3167G>A
NM_001130987.2:c.3167G>A
NM_003494.3:c.3113G>A
O75923:p.Arg1038Gln

Protein change:

R1024Q

Links:

UniProtKB: O75923#VAR_024862; dbSNP: rs150877497

NCBI 1000 Genomes Browser:

rs150877497

Molecular consequence:

NM_001130455.2:c.3116G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130976.2:c.3071G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130977.2:c.3071G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130978.2:c.3113G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130979.2:c.3206G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130980.2:c.3164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130981.2:c.3164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130982.2:c.3209G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130983.2:c.3116G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130984.2:c.3074G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130985.2:c.3167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130986.2:c.3074G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130987.2:c.3167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003494.4:c.3113G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Qualitative or quantitative defects of dysferlin
Synonyms:: Dysferlinopathy
Identifiers:: MONDO: MONDO:0016145; MedGen: C2931687

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000649653	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 7, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14678801, 18832576, 18853459, 25591676, 27821570, 28492532
SCV000914939	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27821570, 18853459, 18276788, 14678801, 25591676, 25868377 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000649653

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 7, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000914939

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Apr 28, 2017)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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

Dysferlin deficiency shows compensatory induction of Rab27A/Slp2a that may contribute to inflammatory onset.

Kesari A, Fukuda M, Knoblach S, Bashir R, Nader GA, Rao D, Nagaraju K, Hoffman EP.

Am J Pathol. 2008 Nov;173(5):1476-87. doi: 10.2353/ajpath.2008.080098. Epub 2008 Oct 2.

PubMed [citation]

PMID:: 18832576
PMCID:: PMC2570137

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000649653.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). This variant is present in population databases (rs150877497, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This variant is also known as p.Arg1056Gln. ClinVar contains an entry for this variant (Variation ID: 242418). 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 expected to disrupt DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 27821570). For these reasons, this variant has been classified as Pathogenic.

#	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 Illumina Laboratory Services, Illumina, SCV000914939.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including one homozygote, four presumed compound heterozygotes, one patient where four other variants in this gene were also identified, one heterozygote, and two patients in whom the genotypes were not specified (Cagliani et al. 2003; Nagaraju et al. 2008; Krahn et al. 2009; Xi et al. 2014; Shin et al. 2015 and Quinn et al. 2016). The p.Arg1038Gln variant was absent from 300 control chromosomes and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of protein from muscle tissue revealed 4% residual dysferlin compared to wild type (Cagliani et al. 2003). Based on the collective evidence, the p.Arg1038Gln variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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: Oct 26, 2024

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