Submissions for variant NM_024301.5(FKRP):c.899T>C (p.Val300Ala)

gnomAD frequency: 0.00004  dbSNP: rs104894691

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000004453	SCV000796383	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2017-12-12	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000732974	SCV000860976	likely pathogenic	not provided	2018-05-11	criteria provided, single submitter	clinical testing
Invitae	RCV000814162	SCV000954563	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 300 of the FKRP protein (p.Val300Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 14647208, 15060126, 24447024). 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: 4232). 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.Val300 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647208, 27848944; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000732974	SCV001250134	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000732974	SCV001770745	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 24447024, 15060126, 20961759, 31268217, 31589614, 27439679, 14647208, 18645206)
Revvity Omics, Revvity	RCV000732974	SCV002017780	likely pathogenic	not provided	2020-10-02	criteria provided, single submitter	clinical testing
DASA	RCV001813735	SCV002061304	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2022-01-05	criteria provided, single submitter	clinical testing	The c.899T>C;p.(Val300Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4232; PMID: 14647208; 15060126; 18645206;20961759; 24447024) - PS4.This variant is not present in population databases (rs104894691, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Val300Ala) was detected in trans with a pathogenic variant (PMID: 24447024; 15060126; 14647208) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Ambry Genetics	RCV002371759	SCV002683737	pathogenic	Cardiovascular phenotype	2022-07-13	criteria provided, single submitter	clinical testing	The p.V300A pathogenic mutation (also known as c.899T>C), located in coding exon 1 of the FKRP gene, results from a T to C substitution at nucleotide position 899. The valine at codon 300 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in individuals with limb-girdle muscular dystrophy (LGMD), as either homozygous or compound heterozygous with an additional known pathogenic mutation in FKRP (de Paula F et al. Eur J Hum Genet, 2003 Dec;11:923-30; Walter MC et al. J Med Genet, 2004 Apr;41:e50; Stensland E et al. Neuromuscul Disord, 2011 Jan;21:41-6). Additionally, an in vitro assay showed this alteration may impact protein function (Henriques SF et al. Hum Mutat, 2019 10;40:1874-1885). Another alteration at the same codon, p.V300M (c.898G>A), has been detected in the homozygous and compound heterozygous states with pathogenic variants in individuals reported to have LGMD or clinical suspicion of LGMD (de Paula F et al. Eur. J. Hum. Genet., 2003 Dec;11:923-30; Frosk P et al. Hum. Mutat., 2005 Jan;25:38-44; Nallamilli BRR et al. Ann Clin Transl Neurol, 2018 Dec;5:1574-1587; Invitae pers. comm.). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482826	SCV002799647	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy type B5; Autosomal recessive limb-girdle muscular dystrophy type 2I; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2021-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155013	SCV003844232	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-02-25	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.899T>C (p.Val300Ala) 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 6.4e-06 in 155278 control chromosomes (gnomAD). c.899T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. de Paula_2003, Walter_2004, Stensland_2011). These data indicate that the variant is very likely to be associated with disease. When glycosylation activity levels were experimentally assessed, the variant performed similarly to a null mutant (Henriques_2019). Ten ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic, and six as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003466810	SCV004197404	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2023-09-19	criteria provided, single submitter	clinical testing
OMIM	RCV000004453	SCV000024626	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2003-12-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000004453	SCV001456654	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-09-16	no assertion criteria provided	clinical testing