rs121908110

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_024301.5(FKRP):c.1387A>G(p.Asn463Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,601,298 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. N463I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.29

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 15 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, 10 uncertain 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 chr19-46756839-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1957901.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

PP5

Variant 19-46756837-A-G is Pathogenic according to our data. Variant chr19-46756837-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756837-A-G is described in Lovd as [Pathogenic]. Variant chr19-46756837-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.1387A>G	p.Asn463Asp	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.1387A>G	p.Asn463Asp	missense_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.1387A>G	p.Asn463Asp	missense_variant	4/4	2		P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-4996A>G		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+8172A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

222240

Hom.:

AF XY:

0.0000822

AC XY:

AN XY:

121698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000840

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:

0.0000235

AC:

AN:

1449154

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

719938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000768

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:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2021	Published functional study demonstrates c.1387A>G showed significantly decreased to absent glycosylated alpha-DG positivity with IIH6 antibody, and mild, variable decreases in beta-DG, dystrophin, and merosin (Lee et al., 2019); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 4235; ClinVar); 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: 31041397, 17336067, 29065428, 31980526) -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 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

Jan 28, 2023

Variant summary: FKRP c.1387A>G (p.Asn463Asp) 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 0.00012 in 222240 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00012 vs 0.0024), allowing no conclusion about variant significance. c.1387A>G has been reported in the literature as a frequent founder variant of Mexican origin in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, PMID: 31931849, 31041397, 34653404). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although in one study, all muscle biopsies from homozygous individuals available for review showed end-stage dystrophic pathology, near absence of glycosylated alpha-dystroglycan (alpha-DG) by immunofluorescence, and reduced molecular weight of alpha-DG compared with controls (PMID: 31041397). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 15, 2015

- -

Muscular dystrophy-dystroglycanopathy type B5

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 28, 2020

The homozygous p.Asn463Asp variant in FKRP was identified by our study in an individual with muscular dystrophy-dystroglycanopathy (PMID: 31041397). The p.Asn463Asp variant has also been reported in at least 13 additional individuals with Hispanic or Mexican ancestry and muscular dystrophy-dystroglycanopathy, segregated with disease in 6 affected relatives from 3 families (PMID: 29065428, 31041397), and has been identified in 0.084% (27/32138) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908110). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported pathogenic by UChicago, EGL Genetic Diagnostics, Invitae, and OMIM in ClinVar (Variation ID: 4235). The presence of this variant in 9 affected homozygotes and in combination with a reported pathogenic variant and in 5 individuals with muscular dystrophy-dystroglycanopathy increases the likelihood that the p.Asn463Asp variant is pathogenic (PMID: 17336067, 29065428, 31041397, 31671740). In vitro functional studies provide some evidence that the p.Asn463Asp variant may impact protein function (PMID: 31041397). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for muscular dystrophy-dystroglycanopathy in an autosomal recessive manner based on the occurrence of this variant with other pathogenic variants in trans, functional evidence showing an affect to protein function, and segregation among multiple families. ACMG/AMP Criteria applied: PM3_Strong, PS3_moderate, PP1_strong, PP3 (Richards 2015). -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 17, 2023

- -

Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2024

The p.N463D pathogenic mutation (also known as c.1387A>G), located in coding exon 1 of the FKRP gene, results from an A to G substitution at nucleotide position 1387. The asparagine at codon 463 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported in the homozygous state in multiple individuals with congenital muscular dystrophy, including hypotonia, motor delay, and elevated CK (MacLeod H et al. Neuromuscul. Disord., 2007 Apr;17:285-9; Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450; Lee AJ et al. Neurol Genet, 2019 Apr;5:e315). In addition, this variant has been reported in trans with a second FKRP alteration (Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450; Lee AJ et al. Neurol Genet, 2019 Apr;5:e315). It has been suggested that this might be a founder allele in individuals with Latino ancestry (Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450). Muscle biopsy from individuals homozygous for this alteration showed myopathic changes including variation in myofiber size, fatty replacement and endomysial fibrosis, absent alpha-dystroglycan staining, reduction in beta-dystroglycan as well as alpha-, beta-, and gamma-sarcoglycan staining, and mild focal reduction of dystrophin and merosin staining (MacLeod H et al. Neuromuscul. Disord., 2007 Apr;17:285-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Invitae

Jan 06, 2024

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 463 of the FKRP protein (p.Asn463Asp). This variant is present in population databases (rs121908110, gnomAD 0.09%). This missense change has been observed in individual(s) with congenital muscular dystrophy and/or limb-girdle muscular dystrophy (PMID: 17336067; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Mexican ancestry (PMID: 17336067; Invitae). ClinVar contains an entry for this variant (Variation ID: 4235). 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Uncertain

0.11

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.61

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.97

MPC

1.7

ClinPred

0.64

GERP RS

5.4

Varity_R

0.85

gMVP

0.88

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