rs121908110

Variant names:

• chr19-46756837-A-G
• rs121908110
• NM_024301.5:c.1387A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.29
• Publications: 12 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: Pathogenic. The variant received 14 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46756838-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1516962.Status of the report is criteria_provided_single_submitter, 1 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, 0.775
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.1387A>G	p.Asn463Asp	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.1387A>G	p.Asn463Asp	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.1387A>G	p.Asn463Asp	missense_variant	Exon 4 of 4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-4996A>G		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5	n.247+8172A>G		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000121 AC: 27 AN: 222240 AF XY: 0.0000822

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000235 AC: 34 AN: 1449154 Hom.: 0 Cov.: 32 AF XY: 0.0000167 AC XY: 12 AN XY: 719938

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.000768 AC: 33 AN: 42956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 84692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106498

Other (OTH) AF: 0.00 AC: 0 AN: 59868

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.000197 AC: 3 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 25, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Muscular dystrophy-dystroglycanopathy type B5 Pathogenic:2

May 28, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Jun 02, 2023

3billion

Significance: 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: 0.012%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000004235 /PMID: 17336067) and different missense changes at the same codon (p.Asn463Ile, p.Asn463Lys, p.Asn463Ser / ClinVar ID: VCV001066164, VCV001516962, VCV001957901) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Oct 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 28, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 15, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5 Pathogenic:1

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Feb 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data database). 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; internal data database). ClinVar contains an entry for this variant (Variation ID: 4235). 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%. 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	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	.;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.65	T
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	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.88
Mutation Taster		=1/99	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: rs121908110; hg19: chr19-47260094;