Submissions for variant NM_024301.5(FKRP):c.235G>A (p.Val79Met)

gnomAD frequency: 0.00435  dbSNP: rs104894683

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000236146	SCV000230415	benign	not specified	2017-04-12	criteria provided, single submitter	clinical testing
Invitae	RCV001083979	SCV000290695	benign	Walker-Warburg congenital muscular dystrophy	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000513718	SCV000293454	benign	not provided	2020-02-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22995991, 18645206, 17113772, 14647208, 25898921)
Genetic Services Laboratory, University of Chicago	RCV000236146	SCV000594778	likely benign	not specified	2015-12-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513718	SCV000610960	likely benign	not provided	2017-05-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000236146	SCV001157673	uncertain significance	not specified	2018-10-23	criteria provided, single submitter	clinical testing	The FKRP c.235G>A; p.Val79Met variant (rs104894683) is reported in several individuals affected with limb girdle muscular dystrophy (de Paula 2003), including three siblings that carried the p.Val79Met variant in trans to a nonsense variant (Vieira 2006). Of the three siblings, two were severely affected and also carried a p.Pro89Ala variant, which was not identified in the third mildly affected sibling (Vieira 2006). The p.Val79Met variant is reported in ClinVar (Variation ID: 4229) and is found in the African population with an overall allele frequency of 1.5% (320/21382 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 79 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val79Met variant is uncertain at this time. References: de Paula F et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003 Dec;11(12):923-30. Vieira NM et al. Mutation analysis in the FKRP gene provides an explanation for a rare cause of intrafamilial clinical variability in LGMD2I. Neuromuscul Disord. 2006 Dec;16(12):870-3.
Ambry Genetics	RCV002444421	SCV002733182	likely benign	Cardiovascular phenotype	2019-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236146	SCV005039461	likely benign	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.235G>A (p.Val79Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 1590552 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. ClinVar contains an entry for this variant (Variation ID: 4229). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000004450	SCV000024623	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2003-12-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000004450	SCV001460331	benign	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-01-10	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000236146	SCV002034615	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000513718	SCV002036078	likely benign	not provided		no assertion criteria provided	clinical testing