rs1450841129

Positions:

• chr19-46756466-G-A
• chr19-46756466-G-C
• chr19-46756466-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_024301.5(FKRP):​c.1016G>A​(p.Arg339His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000049 in 1,427,414 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R339L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.40

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 19-46756466-G-A is Pathogenic according to our data. Variant chr19-46756466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558504.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr19-46756466-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.1016G>A	p.Arg339His	missense_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.1016G>A	p.Arg339His	missense_variant	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7	c.1016G>A	p.Arg339His	missense_variant	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5	n.247-5367G>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7801G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1427414 Hom.: 0 Cov.: 32 AF XY: 0.00000566 AC XY: 4 AN XY: 706248

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: 0.00000639

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

The p.R339H variant (also known as c.1016G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 1016. The arginine at codon 339 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the compound heterozygous state with a frameshift variant and a known pathogenic variant in FKRP in individuals reported to have muscular dystrophy phenotypes (Brockington M et al. Am J Hum Genet, 2001 Dec;69:1198-209; Carlson CR et al. Neurology, 2017 Dec;89:2374-2380; Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803; Murphy LB et al. Ann Clin Transl Neurol, 2020 05;7:757-766). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 339 of the FKRP protein (p.Arg339His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital muscular dystrophy and/or limb-girdle muscular dystrophy (PMID: 14742276, 28688748). ClinVar contains an entry for this variant (Variation ID: 558504). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 23, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.59		Loss of MoRF binding (P = 0.0705);Loss of MoRF binding (P = 0.0705);
MVP		0.96
MPC		1.8
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.86
gMVP		0.85

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

Other links and lift over

dbSNP: rs1450841129; hg19: chr19-47259723;