ClinVar Miner

Submissions for variant NM_016729.3(FOLR1):c.493+2T>C (rs144637717)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235166 SCV000241008 uncertain significance not specified 2017-06-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FOLR1 gene. The c.493+2 T>C variant in the FOLR1 gene has been previously reported in a family with severe intellectual disability; however, additional information was not provided (Najmabadi et al., 2011). This variant is expected to destroy the canonical splice donor site in intron 4 and result in abnormal gene splicing. However, the c.493+2 T>C variant is observed in 226/16,512 (1.4%) alleles from individuals of South Asian background, including multiple unrelated homozygous individuals in large population cohorts, which is greater than expected for this disorder (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081793 SCV000280715 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081793 SCV000331322 uncertain significance not provided 2015-11-23 criteria provided, single submitter clinical testing
Invitae RCV000356764 SCV000648581 benign Cerebral folate transport deficiency 2020-11-30 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000356764 SCV000743881 pathogenic Cerebral folate transport deficiency 2014-10-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716568 SCV000847409 uncertain significance History of neurodevelopmental disorder 2019-12-06 criteria provided, single submitter clinical testing The c.493+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 3 in the FOLR1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In one study, this alteration was detected as homozygous in three siblings from a consanguineous family with symptoms of cerebral folate transport deficiency (Najmabadi H et al. Nature, 2011 Oct;478:57-63). This variant occurred in the homozygous state in a reportedly healthy mother of three heterozygous daughters, one described as having clinical Rett syndrome, and two with autism and epilepsy (Ramaekers VT et al. Mol Genet Metab. 2018 May;124(1):87-93). Based on data from gnomAD, this variant has an overall frequency of approximately 0.31% (861/277102) and has been seen as homozygous in 10 individuals. The highest observed frequency was 1.4% (434/30780) in the South Asian subpopulation. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000356764 SCV001268708 uncertain significance Cerebral folate transport deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Institute Rare Disease Group, Broad Institute RCV000356764 SCV001435221 benign Cerebral folate transport deficiency criteria provided, single submitter research The homozygous c.493+2T>C variant in FOLR1 and has been identified in at least 1 individual with intellectual disability (PMID: 21937992), and has been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC ( In summary, this variant meets criteria to be classified as benign for autosomal recessive folate receptor deficiency.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000356764 SCV000733110 pathogenic Cerebral folate transport deficiency no assertion criteria provided clinical testing
SingHealth Duke-NUS Institute of Precision Medicine RCV000356764 SCV000853162 uncertain significance Cerebral folate transport deficiency 2017-06-07 no assertion criteria provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000781973 SCV000920428 uncertain significance Seizures 2017-08-25 no assertion criteria provided clinical testing

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