chr19-46756348-G-A

Position:

chr19-46756348-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

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 Pathogenic.

Frequency

Genomes: 𝑓 0.00034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:7

Conservation

PhyloP100: 3.91

Variant links:

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 links:

FKRP (HGNC:):

FKRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a region_of_interest Zinc finger loop (size 29) in uniprot entity FKRP_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_024301.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46756349-T-C is described in Lovd as [Pathogenic].

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 id is 241460.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=2, Likely_pathogenic=6}. Variant chr19-46756348-G-A is described in Lovd as [Pathogenic]. Variant chr19-46756348-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.898G>A	p.Val300Met	missense_variant	4/4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.898G>A	p.Val300Met	missense_variant	4/4	1	NM_024301.5	ENSP00000326570.4	Q9H9S5
FKRP	ENST00000391909.7 linkuse as main transcript	c.898G>A	p.Val300Met	missense_variant	4/4	2		ENSP00000375776.2	Q9H9S5
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5485G>A		intron_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7683G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

155130

Hom.:

AF XY:

0.0000117

AC XY:

AN XY:

85216

show subpopulations

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 SAS 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:

AN:

1406868

Hom.:

Cov.:

AF XY:

0.0000244

AC XY:

AN XY:

695532

show subpopulations

Gnomad4 AFR exome

AF:

0.000924

Gnomad4 AMR exome

AF:

0.000191

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.20e-7

Gnomad4 OTH exome

AF:

0.0000856

GnomAD4 genome

AF:

0.000335

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0000474

Hom.:

Bravo

AF:

0.000450

ExAC

AF:

0.0000271

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 26, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	FKRP: PM2, PM3, PM5, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2023	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 01, 2021	PP3, PM2, PM3, PM5, PS4_supporting -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Inheritance Genetic Center	Jul 09, 2024	- -

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 03, 2024	- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 21, 2021

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 (congenital with brain and eye anomalies), type A5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

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; 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Walker-Warburg congenital muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2015

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.82

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

GERP RS

3.1

Varity_R

0.50

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over