19-46756523-C-T

Variant names:

• chr19-46756523-C-T
• rs143031195
• NM_024301.5:c.1073C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_024301.5(FKRP):​c.1073C>T​(p.Pro358Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000828 in 1,595,158 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). Synonymous variant affecting the same amino acid position (i.e. P358P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:6
• Conservation: PhyloP100: 7.41
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in FKRP

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 19-46756523-C-T is Pathogenic according to our data. Variant chr19-46756523-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167072.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.1073C>T	p.Pro358Leu	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.1073C>T	p.Pro358Leu	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.1073C>T	p.Pro358Leu	missense_variant	Exon 4 of 4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5310C>T		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5	n.247+7858C>T		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000141 AC: 30 AN: 213340 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000340

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000526

Gnomad OTH exome AF: 0.000559

GnomAD4 exome AF: 0.0000804 AC: 116 AN: 1442964 Hom.: 0 Cov.: 32 AF XY: 0.0000796 AC XY: 57 AN XY: 715990

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.0000249 AC: 1 AN: 40178

Ashkenazi Jewish (ASJ) AF: 0.00274 AC: 70 AN: 25576

East Asian (EAS) AF: 0.00 AC: 0 AN: 39020

South Asian (SAS) AF: 0.00 AC: 0 AN: 83176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000244 AC: 27 AN: 1104866

Other (OTH) AF: 0.000301 AC: 18 AN: 59806

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74352

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Jun 27, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in apparently homozygous or compound heterozygous state in patients with limb-girdle muscular dystrophy (LGMD) or dystroglycanopathies in published literature (PMID: 16344347, 37476387, 35239206, 32115343, 32429923, 17952692, 14647208, 18645206); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21293871, 25898921, 31638414, 32342672, 18645206, 30564623, 27439679, 37154180, 14647208, 17952692, 32115343, 35239206, 32429923, 37476387, 16344347, 38127101, 30709774) -

Mar 28, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Pro358Leu (c.1073C>T) in the FKRP gene. This variant was seen in a patient in our clinic with atrial fibrillation. Testing was performed at Invitae. Given the lack of known gene-phenotype association, lack of case data, and overall frequency in the general population, we consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). At this time there is no data to connect it to atrial fibrillation that we are aware of. It may be an autosomal recessive allele for muscular dystrophy, however Invitae currently considers it a variant of uncertain significance even for that. There is an entry in ClinVar from Emory; it is classified by themas variant of uncertain significance. Per the lab report, "The FKRP gene is associated with autosomal recessive muscular dystrophy-dystroglycanopathy type A5 (MDDGA5) (MedGen UID:461763), type B5 (MDDGB5) (MedGen UID:335764), and type C5) (MedGen UID:339580), and dilated cardiomyopathy (DCM) (MedGen UID:2880)." The lab report notes that the variant has been reported in multiple individuals with limb girdle muscular dystrophy (LGMD), however the frequency in the general population raises the question of whether this could be a benign ethnicity-specific variant (see below). Boito et al. (2005) observed the variant in 3 of 214 patients recruited in Italy and both were compound heterozygotes, consistent with the autosomal recessive inheritance previously reported for FKRP in LGMD. De Paula et al. (2003) also reported a compound heterozygote for this variant who had LGMD (recruited in Brazil). Per the lab report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably"; Align-GVGD: "Class C0")." The variant was reported online in 32 of 119,683 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The absence of calls for 20,000 individuals in gnomAD may indicate that it is a low-quality site. It is by far most common in Ashkenazi Jewish individuals, such as our patient. Specifically, the variant was observed in 22/4,629 Ashkenazi Jewish individuals, for an ethnicity-specific allele frequency of 0.24%. (This would predict an autosomal recessive disease prevalence of ~1/175,000.) It was also observed in 6 non-Finnish Europeans, 2 “Other” ancestry, 1 African, and 1 Latino. Overall allele frequency: 0.013%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:3

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 26, 2023

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Sep 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FKRP c.1073C>T (p.Pro358Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 213340 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00014 vs 0.0024), allowing no conclusion about variant significance. c.1073C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive or FKRP-related disorders. Multiple patients also carry another pathogenic FKRP variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

FKRP-related disorder Pathogenic:1

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FKRP c.1073C>T variant is predicted to result in the amino acid substitution p.Pro358Leu. This variant has been reported the compound heterozygous state in at least three individuals and in the homozygous state in one individual with FKRP-related disorders (de Paula. 2003. PubMed ID: 14647208; Boito et al 2005. PubMed ID: 16344347; Boito et al. 2007. PubMed ID: 17952692). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -

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

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 358 of the FKRP protein (p.Pro358Leu). This variant is present in population databases (rs143031195, gnomAD 0.2%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 14647208, 16344347, 17952692; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167072). 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. -

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 Uncertain:1

Apr 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Jul 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P358L variant (also known as c.1073C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 1073. The proline at codon 358 is replaced by leucine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with additional alterations in FKRP in individuals with concerns for muscular dystrophies, including limb girdle muscular dystrophy; however, clinical details were limited in some cases (de Paula F et al. Eur J Hum Genet, 2003 Dec;11:923-30; Boito CA et al. Arch Neurol, 2005 Dec;62:1894-9; Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803; Wu L et al. Can J Neurol Sci, 2018 May;45:262-268; Murphy LB et al. Ann Clin Transl Neurol, 2020 May;7:757-766; Krenn M et al. Eur J Neurol, 2022 Jun;29:1815-1824; Gonzalez-Perez P et al. Neuromuscul Disord, 2020 Mar;30:213-218). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M
PhyloP100		7.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-9.7	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.95
MVP		0.96
MPC		1.7
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs143031195; hg19: chr19-47259780;