NM_024301.5(FKRP):c.540_570dup (p.Cys191fs) AND Walker-Warburg congenital muscular dystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 4, 2023
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:: RCV001383495.7

Allele description [Variation Report for NM_024301.5(FKRP):c.540_570dup (p.Cys191fs)]

NM_024301.5(FKRP):c.540_570dup (p.Cys191fs)

Gene:

FKRP:fukutin related protein [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

19q13.32

Genomic location:

Preferred name:

NM_024301.5(FKRP):c.540_570dup (p.Cys191fs)

HGVS:

NC_000019.10:g.46755990_46756020dup
NG_008898.2:g.14945_14975dup
NM_001039885.3:c.540_570dup
NM_024301.5:c.540_570dupMANE SELECT
NP_001034974.1:p.Cys191fs
NP_077277.1:p.Cys191fs
LRG_761t1:c.540_570dup
LRG_761:g.14945_14975dup
LRG_761p1:p.Cys191fs
NC_000019.9:g.47259242_47259243insCCGCCCGCTATGGCGCAGCCCCCGCCGCGCC
NC_000019.9:g.47259247_47259277dup

Protein change:

C191fs

Links:

dbSNP: rs1311148380

NCBI 1000 Genomes Browser:

rs1311148380

Molecular consequence:

NM_001039885.3:c.540_570dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024301.5:c.540_570dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Walker-Warburg congenital muscular dystrophy
Synonyms:: Muscular dystrophy-dystroglycanopathy, type A; Walker-Warburg syndrome
Identifiers:: MONDO: MONDO:0000171; MedGen: C0265221; Orphanet: 899; OMIM: PS236670

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001582646	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 4, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 34509255, 11592034, 12666124, 12707425, 14742276, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001582646

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 4, 2023)

germline

clinical testing

PubMed (6)
[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

FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients.

Awano H, Saito Y, Shimizu M, Sekiguchi K, Niijima S, Matsuo M, Maegaki Y, Izumi I, Kikuchi C, Ishibashi M, Okazaki T, Komaki H, Iijima K, Nishino I.

J Clin Neurosci. 2021 Oct;92:215-221. doi: 10.1016/j.jocn.2021.08.014. Epub 2021 Aug 28.

PubMed [citation]

PMID:: 34509255

Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan.

Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, Ponting CP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F.

Am J Hum Genet. 2001 Dec;69(6):1198-209. Epub 2001 Oct 8.

PubMed [citation]

PMID:: 11592034
PMCID:: PMC1235559

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001582646.4

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

Description

ClinVar contains an entry for this variant (Variation ID: 1071118). This sequence change creates a premature translational stop signal (p.Cys191Profs*78) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 305 amino acid(s) of the FKRP protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 34509255). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Ser385*) have been determined to be pathogenic (PMID: 11592034, 12666124, 12707425, 14742276). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

Last Updated: Sep 29, 2024

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