NM_024301.5(FKRP):c.947C>G (p.Pro316Arg) AND Walker-Warburg congenital muscular dystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 26, 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:: RCV001065681.7

Allele description [Variation Report for NM_024301.5(FKRP):c.947C>G (p.Pro316Arg)]

NM_024301.5(FKRP):c.947C>G (p.Pro316Arg)

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.947C>G (p.Pro316Arg)

HGVS:

NC_000019.10:g.46756397C>G
NG_008898.2:g.15352C>G
NM_001039885.3:c.947C>G
NM_024301.5:c.947C>GMANE SELECT
NP_001034974.1:p.Pro316Arg
NP_077277.1:p.Pro316Arg
LRG_761t1:c.947C>G
LRG_761:g.15352C>G
LRG_761p1:p.Pro316Arg
NC_000019.9:g.47259654C>G
NM_024301.4:c.947C>G
Q9H9S5:p.Pro316Arg

Protein change:

P316R

Links:

UniProtKB: Q9H9S5#VAR_018289; dbSNP: rs752582904

NCBI 1000 Genomes Browser:

rs752582904

Molecular consequence:

NM_001039885.3:c.947C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024301.5:c.947C>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
SCV001230652	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11592034, 11741828, 25135358, 12654965, 12666124, 16368217, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001230652

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2023)

germline

clinical testing

PubMed (7)
[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

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

Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C.

Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S, Benson MA, Herrmann R, Anderson LV, Bashir R, Burgunder JM, Fallet S, Romero N, Fardeau M, Straub V, Storey G, Pollitt C, Richard I, Sewry CA, Bushby K, Voit T, Blake DJ, Muntoni F.

Hum Mol Genet. 2001 Dec 1;10(25):2851-9.

PubMed [citation]

PMID:: 11741828

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001230652.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant is present in population databases (rs752582904, gnomAD 0.002%). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 11592034, 11741828, 16368217, 25135358). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197347). 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 FKRP protein function. This variant disrupts the p.Pro316 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been observed in individuals with FKRP-related conditions (PMID: 12654965, 12666124, 16368217), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 316 of the FKRP protein (p.Pro316Arg).

#	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: Mar 30, 2024

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