rs1290836394

Positions:

• chr19-46755605-T-TGGTGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024301.5(FKRP):​c.158_162dup​(p.Glu55CysfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,453,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FKRP NM_024301.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.372

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]

ACMG classification

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 176 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-46755605-T-TGGTGC is Pathogenic according to our data. Variant chr19-46755605-T-TGGTGC is described in ClinVar as [Pathogenic]. Clinvar id is 459232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.158_162dup	p.Glu55CysfsTer15	frameshift_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.158_162dup	p.Glu55CysfsTer15	frameshift_variant	4/4	1	NM_024301.5	ENSP00000326570	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1453776 Hom.: 0 Cov.: 33 AF XY: 0.0000111 AC XY: 8 AN XY: 722944

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: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 20, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 04, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2020

The c.158_162dupTGCGG pathogenic mutation, located in coding exon 1 of the FKRP gene, results from a duplication of TGCGG at nucleotide position 158, causing a translational frameshift with a predicted alternate stop codon (p.E55Cfs*15). This alteration occurs at the 3' terminus of theFKRP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 89% (442 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was detected as compound heterozygous with another variant in FKRP (p.W231C, c.693G>C) in an individual with congenital muscular dystrophy without mental retardation (Sframeli M et al. Neuromuscul. Disord., 2017 Sep;27:793-803). This variant was also detected as compound heterozygous with FKRP p.L276I (c.826C>A) in an individual with limb-girdle muscular dystrophy (LGMD) type 2I (Sveen ML et al. Ann. Neurol., 2006 May;59:808-15). In addition, this alteration was reported as compound heterozygous in two individuals with LGMD of unspecified type; however, the other FKRP variants were not described (Sframeli M et al. Neuromuscul. Disord., 2017 Sep;27:793-803). This variant was not reported in population-based 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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change creates a premature translational stop signal (p.Glu55Cysfs*15) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 441 amino acid(s) of the FKRP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy or dystroglycanopathy (PMID: 12666124). ClinVar contains an entry for this variant (Variation ID: 459232). 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1290836394; hg19: chr19-47258862;