rs770711331

Positions:

chr19-46755716-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_024301.5(FKRP):c.266C>T(p.Pro89Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000913 in 1,424,412 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. P89A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000091 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.77

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 Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46755715-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 19-46755716-C-T is Pathogenic according to our data. Variant chr19-46755716-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755716-C-T 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.266C>T	p.Pro89Leu	missense_variant	4/4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.266C>T	p.Pro89Leu	missense_variant	4/4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000154

AC:

AN:

195042

Hom.:

AF XY:

0.0000187

AC XY:

AN XY:

106826

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:

0.0000347

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000913

AC:

AN:

1424412

Hom.:

Cov.:

AF XY:

0.00000848

AC XY:

AN XY:

707232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000241

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000909

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2017	- -

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 09, 2021

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 30, 2021

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 27, 2024

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2024

The p.P89L pathogenic mutation (also known as c.266C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 266. The proline at codon 89 is replaced by leucine, an amino acid with similar 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 (Vieira NM et al. Neuromuscul Disord, 2006 Dec;16:870-3; Quijano-Roy S et al. Brain Dev, 2006 May;28:232-42; Darin N et al. Eur J Paediatr Neurol, 2007 Nov;11:353-7; Wahbi K et al. Neuromuscul Disord, 2008 Aug;18:650-5; Jimenez-Mallebrera C et al. Brain Pathol, 2009 Oct;19:596-611; Carlson CR et al. Neurology, 2017 Dec;89:2374-2380; Murphy LB et al. Ann Clin Transl Neurol, 2020 May;7:757-766; Nallamilli BRR et al. Ann Clin Transl Neurol, 2023 Nov;10:2092-2104). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant 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

Dec 04, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the FKRP protein (p.Pro89Leu). 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 individuals with muscular dystrophy (PMID: 16368217, 17446099, 18639457, 18691338). ClinVar contains an entry for this variant (Variation ID: 551007). 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.Pro89 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been observed in individuals with FKRP-related conditions (PMID: 15833426, 17113772), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D;D;.;.;.;.;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

.;L;L;.;.;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.6

.;D;D;.;.;.;.;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

.;D;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;.;.;.;.;.

Vest4

0.62, 0.72

MutPred

0.85

Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);

MVP

0.96

MPC

1.5

ClinPred

0.97

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.81

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