rs104894691

Positions:

chr19-46756349-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_024301.5(FKRP):c.899T>C(p.Val300Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000269 in 1,559,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V300M) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 5.53

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 chr19-46756348-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 19-46756349-T-C is Pathogenic according to our data. Variant chr19-46756349-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756349-T-C is described in Lovd as [Pathogenic]. Variant chr19-46756349-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.899T>C	p.Val300Ala	missense_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.899T>C	p.Val300Ala	missense_variant	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.899T>C	p.Val300Ala	missense_variant	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5484T>C		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7684T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000644

AC:

AN:

155278

Hom.:

AF XY:

0.00

AC XY:

AN XY:

85270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000249

AC:

AN:

1407096

Hom.:

Cov.:

AF XY:

0.0000216

AC XY:

AN XY:

695610

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000272

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:

0.0000313

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 12, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2018	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 25, 2023

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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2024

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

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. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

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. -

Walker-Warburg congenital muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;D

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

.;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.2

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.96

P;P

Vest4

0.64

MutPred

0.81

Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);

MVP

0.92

MPC

1.4

ClinPred

0.96

GERP RS

4.2

Varity_R

0.77

gMVP

0.89

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