ClinVar Genomic variation as it relates to human health
NM_024301.5(FKRP):c.899T>C (p.Val300Ala)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024301.5(FKRP):c.899T>C (p.Val300Ala)
Variation ID: 4232 Accession: VCV000004232.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 46756349 (GRCh38) [ NCBI UCSC ] 19: 47259606 (GRCh37) [ 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 Jun 12, 2018 Apr 15, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024301.5:c.899T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077277.1:p.Val300Ala missense NM_001039885.3:c.899T>C NP_001034974.1:p.Val300Ala missense NC_000019.10:g.46756349T>C NC_000019.9:g.47259606T>C NG_008898.2:g.15304T>C LRG_761:g.15304T>C LRG_761t1:c.899T>C LRG_761p1:p.Val300Ala Q9H9S5:p.Val300Ala - Protein change
- V300A
- Other names
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- Canonical SPDI
- NC_000019.10:46756348:T:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
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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 |
1026 | 1066 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (3) |
criteria provided, single submitter
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Dec 12, 2017 | RCV000004453.6 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 19, 2022 | RCV000732974.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2022 | RCV001813735.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV000814162.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 25, 2023 | RCV003155013.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 13, 2022 | RCV002371759.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2021 | RCV002482826.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 19, 2023 | RCV003466810.1 |
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. |
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Likely pathogenic
(Dec 12, 2017)
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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: SCV000796383.1
First in ClinVar: Jun 12, 2018 Last updated: Jun 12, 2018 |
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Likely pathogenic
(Oct 02, 2021)
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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: SCV002799647.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 19, 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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GeneDx
Accession: SCV001770745.4
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 24447024, 15060126, 20961759, 31268217, 31589614, 27439679, 14647208, 18645206) (less)
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Likely pathogenic
(Oct 02, 2020)
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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: SCV002017780.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 17, 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: SCV000954563.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 300 of the FKRP protein (p.Val300Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 300 of the FKRP protein (p.Val300Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 14647208, 15060126, 24447024). 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: 4232). 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, 27848944; Invitae). 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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Likely pathogenic
(May 11, 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: SCV000860976.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Jan 05, 2022)
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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
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002061304.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.899T>C;p.(Val300Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4232; PMID: 14647208; 15060126; 18645206;20961759; … (more)
The c.899T>C;p.(Val300Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4232; PMID: 14647208; 15060126; 18645206;20961759; 24447024) - PS4.This variant is not present in population databases (rs104894691, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Val300Ala) was detected in trans with a pathogenic variant (PMID: 24447024; 15060126; 14647208) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Jul 13, 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: SCV002683737.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.V300A pathogenic mutation (also known as c.899T>C), located in coding exon 1 of the FKRP gene, results from a T to C substitution at … (more)
The p.V300A pathogenic mutation (also known as c.899T>C), located in coding exon 1 of the FKRP gene, results from a T to C substitution at nucleotide position 899. The valine at codon 300 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in individuals with limb-girdle muscular dystrophy (LGMD), as either homozygous or compound heterozygous with an additional known pathogenic mutation in FKRP (de Paula F et al. Eur J Hum Genet, 2003 Dec;11:923-30; Walter MC et al. J Med Genet, 2004 Apr;41:e50; Stensland E et al. Neuromuscul Disord, 2011 Jan;21:41-6). Additionally, an in vitro assay showed this alteration may impact protein function (Henriques SF et al. Hum Mutat, 2019 10;40:1874-1885). Another alteration at the same codon, p.V300M (c.898G>A), has been detected in the homozygous and compound heterozygous states with pathogenic variants in individuals reported to have LGMD or clinical suspicion of LGMD (de Paula F et al. Eur. J. Hum. Genet., 2003 Dec;11:923-30; Frosk P et al. Hum. Mutat., 2005 Jan;25:38-44; Nallamilli BRR et al. Ann Clin Transl Neurol, 2018 Dec;5:1574-1587; Invitae pers. comm.). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 25, 2023)
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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: SCV003844232.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: FKRP c.899T>C (p.Val300Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: FKRP c.899T>C (p.Val300Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-06 in 155278 control chromosomes (gnomAD). c.899T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. de Paula_2003, Walter_2004, Stensland_2011). These data indicate that the variant is very likely to be associated with disease. When glycosylation activity levels were experimentally assessed, the variant performed similarly to a null mutant (Henriques_2019). Ten ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic, and six as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 19, 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: SCV004197404.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 01, 2019)
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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: SCV001250134.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2003)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024626.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 12, 2018 |
Comment on evidence:
In a Brazilian woman, from a consanguineous family, with LGMD (MDDGC5; 607155), de Paula et al. (2003) identified a homozygous 899T-C transition in the FKRP … (more)
In a Brazilian woman, from a consanguineous family, with LGMD (MDDGC5; 607155), de Paula et al. (2003) identified a homozygous 899T-C transition in the FKRP gene, resulting in a val300-to-ala (V300A) substitution. She had onset at age 14 years and died from pneumonia at age 33 years. Two clinically unaffected sibs also carried the homozygous V300A mutation; although clinical examination was normal at ages 31 and 29 years, respectively, both had increased serum creatine kinase. The mutation was not identified in 200 control chromosomes. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Limb-girdle muscular dystrophy type 2I
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456654.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Functional and cellular localization diversity associated with Fukutin-related protein patient genetic variants. | Henriques SF | Human mutation | 2019 | PMID: 31268217 |
Clinical exome sequencing: results from 2819 samples reflecting 1000 families. | Trujillano D | European journal of human genetics : EJHG | 2017 | PMID: 27848944 |
Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. | Bögershausen N | Human mutation | 2016 | PMID: 27302555 |
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 |
Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with Limb Girdle Muscular Dystrophy 2I. | Stensland E | Neuromuscular disorders : NMD | 2011 | PMID: 20961759 |
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 |
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 rs104894691 ...
HelpRecord last updated Apr 15, 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.