Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33101984, 31130284, 31268217, 16368217, 28454995, 14652796, 22908982, 23420653, 15574464, 23894383, 18671187, 19955119)
ClinVar Genomic variation as it relates to human health
NM_024301.5(FKRP):c.1364C>A (p.Ala455Asp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024301.5(FKRP):c.1364C>A (p.Ala455Asp)
Variation ID: 4226 Accession: VCV000004226.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 46756814 (GRCh38) [ NCBI UCSC ] 19: 47260071 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 19, 2015 Apr 6, 2024 Mar 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024301.5:c.1364C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077277.1:p.Ala455Asp missense NM_001039885.3:c.1364C>A NP_001034974.1:p.Ala455Asp missense NC_000019.10:g.46756814C>A NC_000019.9:g.47260071C>A NG_008898.2:g.15769C>A LRG_761:g.15769C>A LRG_761t1:c.1364C>A LRG_761p1:p.Ala455Asp Q9H9S5:p.Ala455Asp - Protein change
- A455D
- Other names
- -
- Canonical SPDI
- NC_000019.10:46756813:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| FKRP | - | - |
GRCh38 GRCh37 |
1056 | 1100 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Mar 25, 2024 | RCV000004447.8 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Sep 14, 2015 | RCV000201040.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 25, 2023 | RCV000532707.11 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 8, 2022 | RCV000597675.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 4, 2023 | RCV003466808.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001820318.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); … (more)
Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33101984, 31130284, 31268217, 16368217, 28454995, 14652796, 22908982, 23420653, 15574464, 23894383, 18671187, 19955119) (less)
|
|
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Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: research
|
Muscular dystrophy-dystroglycanopathy type B5
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805414.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
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Pathogenic
(Sep 14, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Limb-girdle muscular dystrophy-dystroglycanopathy, type C5
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000255777.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
|
|
|
Pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000708114.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Sex: mixed
|
|
|
Pathogenic
(Feb 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004197438.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Jul 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023717.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Walker-Warburg congenital muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000630831.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 15574464, 19955119). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 15574464, 19955119). 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: 4226). This missense change has been observed in individuals with congenital muscular dystrophy, limb-girdle muscular dystrophy and muscle-eye brain disease (PMID: 14652796, 16368217, 18671187, 23420653, 23894383). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 455 of the FKRP protein (p.Ala455Asp). (less)
|
|
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Pathogenic
(Jan 03, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000796853.2
First in ClinVar: Oct 19, 2015 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133158.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
Pathogenic
(Feb 01, 2004)
|
no assertion criteria provided
Method: literature only
|
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024620.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 24, 2020 |
Comment on evidence:
In 6 unrelated Tunisian patients with congenital muscular dystrophy (MDDGB5; 606612), previously designated MDC1C, Louhichi et al. (2004) identified a homozygous 1364C-A transversion in the … (more)
In 6 unrelated Tunisian patients with congenital muscular dystrophy (MDDGB5; 606612), previously designated MDC1C, Louhichi et al. (2004) identified a homozygous 1364C-A transversion in the FKRP gene, resulting in an ala455-to-asp (A455D) substitution. All patients came from unrelated consanguineous families. Microsatellite marker analysis suggested a founder effect. In addition to a typical MDC1C phenotype, the patients also had severe psychomotor retardation, mental retardation, and white matter changes and/or cerebellar structural abnormalities on MRI. Louhichi et al. (2004) noted the similarities to the patients reported by Topaloglu et al. (2003) (see 606596.0007-606596.0008). (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 15574464, 19955119). 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: 4226). This missense change has been observed in individuals with congenital muscular dystrophy, limb-girdle muscular dystrophy and muscle-eye brain disease (PMID: 14652796, 16368217, 18671187, 23420653, 23894383). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 455 of the FKRP protein (p.Ala455Asp).
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33101984, 31130284, 31268217, 16368217, 28454995, 14652796, 22908982, 23420653, 15574464, 23894383, 18671187, 19955119)
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 15574464, 19955119). 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: 4226). This missense change has been observed in individuals with congenital muscular dystrophy, limb-girdle muscular dystrophy and muscle-eye brain disease (PMID: 14652796, 16368217, 18671187, 23420653, 23894383). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 455 of the FKRP protein (p.Ala455Asp).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield. | Alfares A | Molecular genetics and metabolism | 2017 | PMID: 28454995 |
| Elevated serum creatine kinase and small cerebellum prompt diagnosis of congenital muscular dystrophy due to FKRP mutations. | Trovato R | Journal of child neurology | 2014 | PMID: 23420653 |
| Flow cytometry for the analysis of α-dystroglycan glycosylation in fibroblasts from patients with dystroglycanopathies. | Stevens E | PloS one | 2013 | PMID: 23894383 |
| Zebrafish models for human FKRP muscular dystrophies. | Kawahara G | Human molecular genetics | 2010 | PMID: 19955119 |
| Variable cardiac involvement in Tunisian siblings harboring FKRP gene mutations. | Kefi M | Neuropediatrics | 2008 | PMID: 18671187 |
| Brain MRI abnormalities in muscular dystrophy due to FKRP mutations. | Quijano-Roy S | Brain & development | 2006 | PMID: 16368217 |
| Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. | Esapa CT | Human molecular genetics | 2005 | PMID: 15574464 |
| 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 | Neurogenetics | 2004 | PMID: 14652796 |
| FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. | Topaloglu H | Neurology | 2003 | PMID: 12654965 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKRP | - | - | - | - |
Text-mined citations for rs28937903 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.