NM_024301.5(FKRP):c.1253G>A (p.Trp418Ter) AND Walker-Warburg congenital muscular dystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 28, 2021
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:: RCV002035498.5

Allele description [Variation Report for NM_024301.5(FKRP):c.1253G>A (p.Trp418Ter)]

NM_024301.5(FKRP):c.1253G>A (p.Trp418Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.32

Genomic location:

Preferred name:

NM_024301.5(FKRP):c.1253G>A (p.Trp418Ter)

HGVS:

NC_000019.10:g.46756703G>A
NG_008898.2:g.15658G>A
NM_001039885.3:c.1253G>A
NM_024301.5:c.1253G>AMANE SELECT
NP_001034974.1:p.Trp418Ter
NP_077277.1:p.Trp418Ter
LRG_761t1:c.1253G>A
LRG_761:g.15658G>A
LRG_761p1:p.Trp418Ter
NC_000019.9:g.47259960G>A

Protein change:

W418*

Links:

dbSNP: rs746533953

NCBI 1000 Genomes Browser:

rs746533953

Molecular consequence:

NM_001039885.3:c.1253G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_024301.5:c.1253G>A - nonsense - [Sequence Ontology: SO:0001587]

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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translocase of chloroplast 90, chloroplastic [Prunus persica]
translocase of chloroplast 90, chloroplastic [Prunus persica]
gi|595802948|ref|XP_007201938.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002229786	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 28, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30919934, 16476814, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002229786

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 28, 2021)

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

Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.

Ten Dam L, Frankhuizen WS, Linssen WHJP, Straathof CS, Niks EH, Faber K, Fock A, Kuks JB, Brusse E, de Coo R, Voermans N, Verrips A, Hoogendijk JE, van der Pol L, Westra D, de Visser M, van der Kooi AJ, Ginjaar I.

Clin Genet. 2019 Aug;96(2):126-133. doi: 10.1111/cge.13544. Epub 2019 May 6.

PubMed [citation]

PMID:: 30919934

Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations.

Mercuri E, Topaloglu H, Brockington M, Berardinelli A, Pichiecchio A, Santorelli F, Rutherford M, Talim B, Ricci E, Voit T, Muntoni F.

Arch Neurol. 2006 Feb;63(2):251-7.

PubMed [citation]

PMID:: 16476814

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002229786.2

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

Description

This sequence change creates a premature translational stop signal (p.Trp418*) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the FKRP protein. This variant is present in population databases (rs746533953, ExAC 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of FKRP-related conditions (PMID: 30919934). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the FKRP protein in which other variant(s) (p.Q460*) have been determined to be pathogenic (PMID: 16476814; Invitae). 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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