ClinVar Genomic variation as it relates to human health
NM_024301.5(FKRP):c.898G>A (p.Val300Met)
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.
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(2); Likely pathogenic(6); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024301.5(FKRP):c.898G>A (p.Val300Met)
Variation ID: 241460 Accession: VCV000241460.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 47259605 (GRCh37) [ NCBI UCSC ] 19: 46756348 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 27, 2017 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024301.5:c.898G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077277.1:p.Val300Met missense NM_001039885.3:c.898G>A NP_001034974.1:p.Val300Met missense NC_000019.10:g.46756348G>A NC_000019.9:g.47259605G>A NG_008898.2:g.15303G>A LRG_761:g.15303G>A LRG_761t1:c.898G>A LRG_761p1:p.Val300Met Q9H9S5:p.Val300Met - Protein change
- V300M
- Other names
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- Canonical SPDI
- NC_000019.10:46756347:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00040 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00031
1000 Genomes Project 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00045
1000 Genomes Project 30x 0.00109
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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FKRP | - | - |
GRCh38 GRCh37 |
1036 | 1078 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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. |
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Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000226616.13 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Apr 17, 2023 | RCV000726141.35 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 16, 2015 | RCV000398763.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 28, 2022 | RCV000672226.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765453.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV003463680.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2021 | RCV001731540.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2022 | RCV002374378.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV003224238.2 |
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
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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. |
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Uncertain significance
(Mar 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000342368.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Walker-Warburg congenital muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000290705.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 300 of the FKRP protein (p.Val300Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 300 of the FKRP protein (p.Val300Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy, and FKRP-related disorders (PMID: 14647208, 27848944; Invitae). 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: 241460). 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 with a positive predictive value of 95%. This variant disrupts the p.Val300 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647208, 15060126, 24447024). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Nov 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000594786.1
First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017 |
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Uncertain significance
(Jan 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000797313.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Dec 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885462.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019 |
Comment:
The FKRP p.Val300Met variant (rs563033008) has been reported in the compound heterozygous state with a known pathogenic FKRP variant in two individuals who were diagnosed … (more)
The FKRP p.Val300Met variant (rs563033008) has been reported in the compound heterozygous state with a known pathogenic FKRP variant in two individuals who were diagnosed with limb girdle muscular dystrophy; however, inheritance information was not provided for these individuals (de Paula 2003, Frosk 2005, and Yamamoto 2008). The p.Val300Met variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.016% (identified in 5 out of 30,820 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 241460). The valine at codon 300 is highly conserved considering 11 species up to fruit fly (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FKRP protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, the available evidence is not sufficient to classify the p.Val300Met variant with certainty. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
Muscular dystrophy-dystroglycanopathy type B5 Autosomal recessive limb-girdle muscular dystrophy type 2I Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896744.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Sep 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983658.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: FKRP c.898G>A (p.Val300Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: FKRP c.898G>A (p.Val300Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 155330 control chromosomes (gnomAD and publication data). c.898G>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, including homozygotes (de Paula_2003, Trujillano_2017, Nallamilli_2018). These data indicate that the variant is likely to be associated with disease. Additionally, another missense variant at the same codon, V300A, was found in individuals affected with autosomal recessive limb-girdle muscular dystrophy, suggesting that this variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Dec 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520070.1
First in ClinVar: May 27, 2022 Last updated: May 27, 2022 |
Comment:
PP3, PM2, PM3, PM5, PS4_supporting
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Likely pathogenic
(Apr 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001815486.2
First in ClinVar: Sep 08, 2021 Last updated: Apr 30, 2023 |
Comment:
Reported in an individual with limb girdle muscular dystrophy (LGMD) who also had a known pathogenic FKRP variant; however, information on the phase of the … (more)
Reported in an individual with limb girdle muscular dystrophy (LGMD) who also had a known pathogenic FKRP variant; however, information on the phase of the two variants was not provided (de Paula et al., 2003; Frosk et al., 2005; Yamamoto et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24447024, 18645206, 15580560, 14647208, 27848944, 30564623, 15060126, 32746448, 27439679) (less)
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Likely pathogenic
(Mar 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498488.13
First in ClinVar: Apr 11, 2022 Last updated: May 12, 2024 |
Comment:
FKRP: PM2, PM3, PM5, PP3
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581281.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3, PM5, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy type B5
Autosomal recessive limb-girdle muscular dystrophy type 2I Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003919965.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
FKRP NM_ 024301.4 exon 4 p.Val300Met (c.898G>A): This variant has been reported in the literature in a compound heterozygous state in one individual with LGMD … (more)
FKRP NM_ 024301.4 exon 4 p.Val300Met (c.898G>A): This variant has been reported in the literature in a compound heterozygous state in one individual with LGMD and in a homozygous state in one individual presenting with developmental delays, microcephaly, and lissencephaly (de Paula 2003 PMID:14677208, Trujillano 2017 PMID:27848944). This variant is present in 0.01% (5/30820) of total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-47259605-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status with recessive disorders, and/or variable expressivity. This variant is present in ClinVar (Variation ID:241460). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004197398.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003832610.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jul 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002683714.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.898G>A (p.V300M) alteration is located in exon 4 (coding exon 1) of the FKRP gene. This alteration results from a G to A substitution … (more)
The c.898G>A (p.V300M) alteration is located in exon 4 (coding exon 1) of the FKRP gene. This alteration results from a G to A substitution at nucleotide position 898, causing the valine (V) at amino acid position 300 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (10/186418) total alleles studied. The highest observed frequency was 0.04% (6/16396) of African alleles. This variant has been detected in the homozygous and compound heterozygous states (in trans) with pathogenic variants in individuals reported to have limb-girdle muscular dystrophy (LGMD) or clinical suspicion of LGMD (de Paula, 2003; Frosk, 2005; Nallamilli, 2018; Invitae pers. comm.). This alteration has also been detected in the heterozygous state in individuals with suspicion of LGMD, and in the homozygous state in a pediatric case with microcephaly and lissencephaly (Trujillano, 2017; Nallamilli, 2018). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. | Burstein DS | Pediatric research | 2021 | PMID: 32746448 |
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
Clinical exome sequencing: results from 2819 samples reflecting 1000 families. | Trujillano D | European journal of human genetics : EJHG | 2017 | PMID: 27848944 |
Variability in pathogenicity prediction programs: impact on clinical diagnostics. | Walters-Sen LC | Molecular genetics & genomic medicine | 2015 | PMID: 25802880 |
Clinical and muscle biopsy findings in Norwegian paediatric patients with limb girdle muscular dystrophy 2I. | Rasmussen M | Acta paediatrica (Oslo, Norway : 1992) | 2014 | PMID: 24447024 |
Muscle protein alterations in LGMD2I patients with different mutations in the Fukutin-related protein gene. | Yamamoto LU | The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society | 2008 | PMID: 18645206 |
The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. | Frosk P | Human mutation | 2005 | PMID: 15580560 |
FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. | Walter MC | Journal of medical genetics | 2004 | PMID: 15060126 |
Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. | de Paula F | European journal of human genetics : EJHG | 2003 | PMID: 14647208 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKRP | - | - | - | - |
Text-mined citations for rs563033008 ...
HelpRecord last updated May 12, 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.