19-46755995-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_024301.5(FKRP):c.545A>G(p.Tyr182Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,547,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y182H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.30

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 14 ACMG points.

PM1

In a strand (size 5) in uniprot entity FKRP_HUMAN there are 5 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 chr19-46755994-T-C is described in Lovd as [Likely_pathogenic].

PP5

Variant 19-46755995-A-G is Pathogenic according to our data. Variant chr19-46755995-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 282247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755995-A-G is described in Lovd as [Pathogenic]. Variant chr19-46755995-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.545A>G	p.Tyr182Cys	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 link	c.545A>G	p.Tyr182Cys	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

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:

0.0000820

AC:

AN:

146318

Hom.:

AF XY:

0.0000863

AC XY:

AN XY:

81140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00103

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:

0.0000136

AC:

AN:

1395912

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

690742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000357

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000460

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151812

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00156

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000338

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000364

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:3

Aug 07, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 27, 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: 0.010%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.84 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000282247 /PMID: 14647208 /3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). A different missense change at the same codon (p.Tyr182His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000285433 /PMID: 28688748). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Oct 07, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3_very_strong, PS4 -

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:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3_VeryStrong+PP1+PP4+PP3_Moderate -

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

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 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Nov 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y182C pathogenic mutation (also known as c.545A>G), located in coding exon 1 of the FKRP gene, results from an A to G substitution at nucleotide position 545. The tyrosine at codon 182 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other FKRP variant(s) in individual(s) with features consistent with FKRP-related dystroglycanopathies; in at least one instance, the variants were identified in trans (de Paula F et al. Eur J Hum Genet, 2003 Dec;11:923-30; Wahbi K et al. Neuromuscul Disord, 2008 Aug;18:650-5; Liang WC et al. Neuromuscul Disord, 2013 Aug;23:675-81; Dai Y et al. Neuromuscul Disord, 2015 Aug;25:617-24; Fu X et al. J Hum Genet, 2016 Dec;61:1013-1020; Wang L et al. Orphanet J Rare Dis, 2018 Aug;13:133; Awano H et al. J Clin Neurosci, 2021 Oct;92:215-221; Song D et al. Clin Genet, 2021 Mar;99:384-395; Xie Z et al. Biomed Res Int, 2018 May;2018:3710814). Other variant(s) at the same codon, p.Y182H (c.544T>C), have been identified in individual(s) with features consistent with FKRP-related dystroglycanopathies (Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803). 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

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 182 of the FKRP protein (p.Tyr182Cys). This variant is present in population databases (rs543163491, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive limb girdle muscular dystrophy (LGMD) (PMID: 28931339). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282247). 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

0.92

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D

Eigen

Benign

-0.019

Eigen_PC

Benign

0.055

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

.;T

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

L;L

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.10

B;B

Vest4

0.88

MutPred

0.80

Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);

MVP

0.96

MPC

1.8

ClinPred

0.30

GERP RS

4.5

Varity_R

0.81

gMVP

0.97

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