NM_024301.5(FKRP):c.1466T>G (p.Leu489Arg) AND Walker-Warburg congenital muscular dystrophy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 13, 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:: RCV001222193.8

Allele description [Variation Report for NM_024301.5(FKRP):c.1466T>G (p.Leu489Arg)]

NM_024301.5(FKRP):c.1466T>G (p.Leu489Arg)

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.1466T>G (p.Leu489Arg)

HGVS:

NC_000019.10:g.46756916T>G
NG_008898.2:g.15871T>G
NM_001039885.3:c.1466T>G
NM_024301.5:c.1466T>GMANE SELECT
NP_001034974.1:p.Leu489Arg
NP_077277.1:p.Leu489Arg
LRG_761t1:c.1466T>G
LRG_761:g.15871T>G
LRG_761p1:p.Leu489Arg
NC_000019.9:g.47260173T>G
NM_024301.4:c.1466T>G

Protein change:

L489R

Links:

dbSNP: rs1555739321

NCBI 1000 Genomes Browser:

rs1555739321

Molecular consequence:

NM_001039885.3:c.1466T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024301.5:c.1466T>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001394283	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 13, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19917824, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001394283

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 13, 2021)

germline

clinical testing

PubMed (2)
[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

Clinical and mutational spectrum of limb-girdle muscular dystrophy type 2I in 11 French patients.

Bourteel H, Vermersch P, Cuisset JM, Maurage CA, Laforet P, Richard P, Stojkovic T.

J Neurol Neurosurg Psychiatry. 2009 Dec;80(12):1405-8. doi: 10.1136/jnnp.2007.141804.

PubMed [citation]

PMID:: 19917824

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001394283.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces leucine with arginine at codon 489 of the FKRP protein (p.Leu489Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 19917824). ClinVar contains an entry for this variant (Variation ID: 555862). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Last Updated: Oct 20, 2024

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