rs563033008

Variant names:

• chr19-46756348-G-A
• rs563033008
• NM_024301.5:c.898G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-46756348-G-A
• chr19-46756348-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3 PP5

The NM_024301.5(FKRP):​c.898G>A​(p.Val300Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000609 in 1,559,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V300A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:7
• Conservation: PhyloP100: 3.91
• Publications: 6 publications found

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in FKRP

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_024301.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46756349-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808
• PP5: Variant 19-46756348-G-A is Pathogenic according to our data. Variant chr19-46756348-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241460.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.898G>A	p.Val300Met	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.898G>A	p.Val300Met	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.898G>A	p.Val300Met	missense_variant	Exon 4 of 4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5485G>A		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5	n.247+7683G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152108 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.0000322 AC: 5 AN: 155130 AF XY: 0.0000117

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000313 AC: 44 AN: 1406868 Hom.: 0 Cov.: 32 AF XY: 0.0000244 AC XY: 17 AN XY: 695532

African (AFR) AF: 0.000924 AC: 30 AN: 32450

American (AMR) AF: 0.000191 AC: 7 AN: 36732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 36950

South Asian (SAS) AF: 0.00 AC: 0 AN: 80300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44462

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5394

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087048

Other (OTH) AF: 0.0000856 AC: 5 AN: 58382

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152218 Hom.: 1 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74426

African (AFR) AF: 0.000674 AC: 28 AN: 41556

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.0000842 Hom.: 0

Bravo AF: 0.000450

ExAC AF: 0.0000271 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:3

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FKRP: PM2, PM3, PM5, PP3 -

Dec 26, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 30, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3, PM5, PS4_supporting -

Mar 03, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported with a second FKRP variant in patients with limb-girdle muscular dystrophy in published literature; however, segregation information was not provided (PMID: 38544359, 18645206, 14647208, 15580560); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24447024, 15580560, 14647208, 30564623, 15060126, 32746448, 37154180, 27439679, 18645206, 37852290, 27848944, 38544359) -

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:2 Uncertain:1

Jan 22, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Feb 28, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2024

Inheritance Genetic Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1 Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Sep 21, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Muscular dystrophy-dystroglycanopathy type B5 Pathogenic:1

Nov 26, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.94 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000241460 /PMID: 14647208 /3billion dataset). A different missense change at the same codon (p.Val300Ala) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004232 /PMID: 14647208). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Apr 14, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V300M variant (also known as c.898G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 898. The valine at codon 300 is replaced by methionine, an amino acid with highly similar properties. 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 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; Lorenzoni PJ et al. Arq Neuropsiquiatr., 2023 Oct;81:922-933; external communication). 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 D et al. Eur. J. Hum. Genet., 2017 02;25:176-182; Nallamilli BRR et al. Ann Clin Transl Neurol, 2018 Dec;5:1574-1587). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

not specified Uncertain:1

Nov 16, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.9	L;L
PhyloP100		3.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.79		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.94
MPC		1.5
ClinPred		0.099	T
GERP RS		3.1
Varity_R		0.50
gMVP		0.84
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs563033008; hg19: chr19-47259605;