ClinVar Miner

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

gnomAD frequency: 0.00435  dbSNP: rs104894683
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Total submissions: 12
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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: IDUA c.235G>A (p.Ala79Thr) results in a non-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 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.235G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1. These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as 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

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