VCV000283038.60 - ClinVar

NM_024301.5(FKRP):c.731G>A (p.Arg244His)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(8); Likely benign(1)

10 out of 12 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024301.5(FKRP):c.731G>A (p.Arg244His)

Variation ID: 283038 Accession: VCV000283038.60

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 46756181 (GRCh38) [ NCBI UCSC ] 19: 47259438 (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	Dec 6, 2016	Jul 13, 2025	Jun 10, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_024301.5:c.731G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077277.1:p.Arg244His	missense
NM_001039885.3:c.731G>A	NP_001034974.1:p.Arg244His	missense
NC_000019.10:g.46756181G>A
NC_000019.9:g.47259438G>A
NG_008898.2:g.15136G>A
LRG_761:g.15136G>A
LRG_761t1:c.731G>A	LRG_761p1:p.Arg244His

... more HGVS ... less HGVS

Protein change

R244H

Other names

Canonical SPDI

NC_000019.10:46756180:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Exome Aggregation Consortium (ExAC) 0.00000

The Genome Aggregation Database (gnomAD) 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00020

1000 Genomes Project 30x 0.00031

The Genome Aggregation Database (gnomAD), exomes 0.00035

Links

ClinGen: CA9532194 dbSNP: rs764641619 VarSome

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
Gene	OMIM	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	1121	1169

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.
Walker-Warburg congenital muscular dystrophy	Likely benign (1)	criteria provided, single submitter	Jan 1, 2025	RCV000457561.11
Autosomal recessive limb-girdle muscular dystrophy type 2I	Uncertain significance (2)	no assertion criteria provided	Jan 12, 2020	RCV000664793.5
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 19, 2025	RCV000331999.12
not provided	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jun 10, 2025	RCV000725201.44
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jan 19, 2024	RCV002379117.3
Autosomal recessive limb-girdle muscular dystrophy type 2I Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Muscular dystrophy-dystroglycanopathy type B5	Uncertain significance (1)	criteria provided, single submitter	Apr 17, 2023	RCV005396872.1

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.
Uncertain significance (Jun 30, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594784.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016

Uncertain significance (Nov 12, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475118.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (2) PubMed: 16344347‚ 17952692

Uncertain significance (Nov 30, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003832608.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024

Uncertain significance (Jan 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002671039.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 16344347‚ 17952692‚ 26990548 Comment: The p.R244H variant (also known as c.731G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide … (more) The p.R244H variant (also known as c.731G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 731. The arginine at codon 244 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a homozygous individual with limb girdle muscular dystrophy, including myalgia, more affected lower limbs than upper, and no muscle hypertrophy; muscle biopsy results showed some reduction in glycosylated alpha-dystroglycan expression compared to controls (Boito CA et al. Arch. Neurol., 2005 Dec;62:1894-9; Boito CA et al. Virchows Arch., 2007 Dec;451:1047-55). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Likely benign (Jan 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Walker-Warburg congenital muscular dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000548508.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 28492532

Uncertain significance (Feb 19, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002598949.2 First in ClinVar: Nov 05, 2022 Last updated: Mar 16, 2025	Publications: PubMed (2) PubMed: 17952692‚ 16344347 Comment: Variant summary: FKRP c.731G>A (p.Arg244His) results in a non-conservative amino acid change located in the fukutin-related protein stem domain (IPR055105) of the encoded protein sequence. … (more) Variant summary: FKRP c.731G>A (p.Arg244His) results in a non-conservative amino acid change located in the fukutin-related protein stem domain (IPR055105) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 57478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKRP causing Autosomal recessive limb-girdle muscular dystrophy type 2I (0.00035 vs 0.011), allowing no conclusion about variant significance. c.731G>A has been reported in the literature in at least one homozygous individual affected with Autosomal recessive limb-girdle muscular dystrophy type 2I (e.g., Boito_2005, Boito_2007), without strong evidence for causality. These data indicate that the variant may be associated with disease. Muscle biopsy analysis of this homozygous patient showed conflicting results indicating that glycosylated alpha-dystroglycan levels were possibly (but not clearly) decreased vs. controls (Boito_2005, Boito_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17952692, 16344347). ClinVar contains an entry for this variant (Variation ID: 283038). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)

Uncertain significance (Jul 10, 2017) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000334847.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 16344347 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKRP Number of individuals with the variant: 4 Zygosity: Single Heterozygote Sex: mixed

Uncertain significance (Jun 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617404.5 First in ClinVar: Dec 19, 2017 Last updated: Jun 22, 2025	Comment: Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (PMID: 17952692); In silico analysis suggests that … (more) Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (PMID: 17952692); In silico analysis suggests that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 26990548, 30564623, 17952692, 16344347, 27439679) (less)

Pathogenic (Sep 01, 2017) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250132.32 First in ClinVar: May 12, 2020 Last updated: Jul 13, 2025	Number of individuals with the variant: 1

Uncertain significance (Apr 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	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 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006057864.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025

Uncertain significance (Jan 12, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Limb-girdle muscular dystrophy type 2I Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460339.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Uncertain significance (Dec 16, 2016) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2I Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788808.2 First in ClinVar: Aug 05, 2018 Last updated: Jun 29, 2025	Publications: PubMed (1) PubMed: 16344347 Comment: This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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Comment:

The p.R244H variant (also known as c.731G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 731. The arginine at codon 244 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a homozygous individual with limb girdle muscular dystrophy, including myalgia, more affected lower limbs than upper, and no muscle hypertrophy; muscle biopsy results showed some reduction in glycosylated alpha-dystroglycan expression compared to controls (Boito CA et al. Arch. Neurol., 2005 Dec;62:1894-9; Boito CA et al. Virchows Arch., 2007 Dec;451:1047-55). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Variant summary: FKRP c.731G>A (p.Arg244His) results in a non-conservative amino acid change located in the fukutin-related protein stem domain (IPR055105) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 57478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKRP causing Autosomal recessive limb-girdle muscular dystrophy type 2I (0.00035 vs 0.011), allowing no conclusion about variant significance. c.731G>A has been reported in the literature in at least one homozygous individual affected with Autosomal recessive limb-girdle muscular dystrophy type 2I (e.g., Boito_2005, Boito_2007), without strong evidence for causality. These data indicate that the variant may be associated with disease. Muscle biopsy analysis of this homozygous patient showed conflicting results indicating that glycosylated alpha-dystroglycan levels were possibly (but not clearly) decreased vs. controls (Boito_2005, Boito_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17952692, 16344347). ClinVar contains an entry for this variant (Variation ID: 283038). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (PMID: 17952692); In silico analysis suggests that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 26990548, 30564623, 17952692, 16344347, 27439679)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine.	Abulí A	Human mutation	2016	PMID: 26990548
Biochemical and ultrastructural evidence of endoplasmic reticulum stress in LGMD2I.	Boito CA	Virchows Archiv : an international journal of pathology	2007	PMID: 17952692
Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I.	Boito CA	Archives of neurology	2005	PMID: 16344347
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKRP	-	-	-	-

Text-mined citations for rs764641619 ...

These 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 Jul 13, 2025

ClinVar Genomic variation as it relates to human health

NM_024301.5(FKRP):c.731G>A (p.Arg244His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs764641619 ...