NM_024301.5(FKRP):c.1363G>T (p.Ala455Ser) AND Walker-Warburg congenital muscular dystrophy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 17, 2020
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:: RCV000700840.6

Allele description [Variation Report for NM_024301.5(FKRP):c.1363G>T (p.Ala455Ser)]

NM_024301.5(FKRP):c.1363G>T (p.Ala455Ser)

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.1363G>T (p.Ala455Ser)

HGVS:

NC_000019.10:g.46756813G>T
NG_008898.2:g.15768G>T
NM_001039885.3:c.1363G>T
NM_024301.5:c.1363G>TMANE SELECT
NP_001034974.1:p.Ala455Ser
NP_077277.1:p.Ala455Ser
LRG_761t1:c.1363G>T
LRG_761:g.15768G>T
LRG_761p1:p.Ala455Ser
NC_000019.9:g.47260070G>T
NM_024301.4:c.1363G>T

Protein change:

A455S

Links:

dbSNP: rs747785577

NCBI 1000 Genomes Browser:

rs747785577

Molecular consequence:

NM_001039885.3:c.1363G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024301.5:c.1363G>T - 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
SCV000829614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 17, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 14652796, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829614

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 17, 2020)

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

New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families.

Louhichi N, Triki C, Quijano-Roy S, Richard P, Makri S, Méziou M, Estournet B, Mrad S, Romero NB, Ayadi H, Guicheney P, Fakhfakh F.

Neurogenetics. 2004 Feb;5(1):27-34. Epub 2003 Dec 2.

PubMed [citation]

PMID:: 14652796
PMCID:: PMC2244647

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, SCV000829614.4

#	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 alanine with serine at codon 455 of the FKRP protein (p.Ala455Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs747785577, ExAC 0.003%). This variant has not been reported in the literature in individuals with FKRP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The p.Ala455 amino acid residue in FKRP has been determined to be clinically significant (PMID: 14652796,¬†15574464,¬†16368217,¬†18671187, 23420653, 23894383). This suggests that variants that disrupt this residue are likely to be causative of disease. 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: Sep 29, 2024

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