Variant 19-46756378-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024301.5(FKRP):c.928G>T(p.Glu310Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,411,748 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E310E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

FKRP
NM_024301.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.518

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.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 162 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-46756378-G-T is Pathogenic according to our data. Variant chr19-46756378-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756378-G-T 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.928G>T	p.Glu310Ter	stop_gained	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.928G>T	p.Glu310Ter	stop_gained	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.928G>T	p.Glu310Ter	stop_gained	4/4	2		P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5455G>T		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7713G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000251

AC:

AN:

159598

Hom.:

AF XY:

0.0000343

AC XY:

AN XY:

87410

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:

0.0000641

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000106

AC:

AN:

1411748

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

697914

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000138

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000379

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000895

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	Observed with a pathogenic variant in published literature but it unknown if these variants occurred in cis or in trans (Poppe et al., 2003); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 186 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15580560, 19900540, 23591631, 12707425) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2019	- -

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

Jul 12, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 13, 2017

- -

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

Mar 31, 2023

Variant summary: FKRP c.928G>T (p.Glu310X) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not expected to cause absense of the protein through nonsense mediated decay, the variant disrupts the last 186 amino acids in the protein sequence. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.948del [p.Cys317fs], c.1027G>T [p.Glu343Ter]). The variant allele was found at a frequency of 2.5e-05 in 159598 control chromosomes (gnomAD). c.928G>T has been reported in the literature as a biallelic genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Poppe_2003, Frosk_2005, Sframeli_2017). These data indicate that the variant may be associated with disease. Experimental evidence confirms the variant results in loss-of-function: homozygous knock-in of the variant human gene in a mouse model of disease was embryonically lethal (Blaeser_2013), despite evidence that the variant does not impact protein production or secretion (Lu_2010). Six ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and five 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

Nov 15, 2023

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2022

The p.E310* variant (also known as c.928G>T), located in coding exon 1 of the FKRP gene, results from a G to T substitution at nucleotide position 928. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration occurs at the 3' terminus of theFKRP gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 186 (38%) amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant has been reported in compound heterozygotes from limb-girdle muscular dystrophy cohorts (Poppe M et al. Neurology, 2003 Apr;60:1246-51; Frosk P et al. Hum Mutat, 2005 Jan;25:38-44; Murphy LB et al. Ann Clin Transl Neurol, 2020 05;7:757-766). Other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with FKRP-related disease (Mercuri E et al. Arch. Neurol., 2006 Feb;63:251-7; Sveen ML et al. Ann Neurol, 2006 May;59:808-15). 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

Invitae

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Glu310*) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 186 amino acid(s) of the FKRP protein. 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 premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy (PMID: 12707425, 15580560). ClinVar contains an entry for this variant (Variation ID: 550361). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FKRP function (PMID: 23591631). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Trp432*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it 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

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.76

MutationTaster

Benign

1.0

D;D

Vest4

0.57

GERP RS

4.2

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