NM_024301.5(FKRP):c.962C>A (p.Ala321Glu) AND Walker-Warburg congenital muscular dystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 27, 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:: RCV002561048.2

Allele description [Variation Report for NM_024301.5(FKRP):c.962C>A (p.Ala321Glu)]

NM_024301.5(FKRP):c.962C>A (p.Ala321Glu)

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.962C>A (p.Ala321Glu)

HGVS:

NC_000019.10:g.46756412C>A
NG_008898.2:g.15367C>A
NM_001039885.3:c.962C>A
NM_024301.5:c.962C>AMANE SELECT
NP_001034974.1:p.Ala321Glu
NP_077277.1:p.Ala321Glu
LRG_761t1:c.962C>A
LRG_761:g.15367C>A
LRG_761p1:p.Ala321Glu
NC_000019.9:g.47259669C>A
NC_000019.9:g.47259669C>A
NM_001039885.2:c.962C>A

Protein change:

A321E

Links:

dbSNP: rs745882222

NCBI 1000 Genomes Browser:

rs745882222

Molecular consequence:

NM_001039885.3:c.962C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024301.5:c.962C>A - 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
SCV003519250	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16143867, 20961759, 31268217, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003519250

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 27, 2023)

germline

clinical testing

PubMed (4)
[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

Limb girdle muscular dystrophy type 2I caused by a novel missense mutation in the FKRP gene presenting as acute virus-associated myositis in infancy.

von der Hagen M, Kaindl AM, Koehler K, Mitzscherling P, Häusler HJ, Stoltenburg-Didinger G, Huebner A.

Eur J Pediatr. 2006 Jan;165(1):62-3. Epub 2005 Sep 6. No abstract available.

PubMed [citation]

PMID:: 16143867

Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with Limb Girdle Muscular Dystrophy 2I.

Stensland E, Lindal S, Jonsrud C, Torbergsen T, Bindoff LA, Rasmussen M, Dahl A, Thyssen F, Nilssen Ø.

Neuromuscul Disord. 2011 Jan;21(1):41-6. doi: 10.1016/j.nmd.2010.08.008. Epub 2010 Oct 18.

PubMed [citation]

PMID:: 20961759

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV003519250.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is present in population databases (rs745882222, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 321 of the FKRP protein (p.Ala321Glu). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 16143867, 20961759). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 31268217). 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. ClinVar contains an entry for this variant (Variation ID: 930906).

#	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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