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

gnomAD frequency: 0.00134  dbSNP: rs144637717

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081793	SCV000241008	benign	not provided	2019-07-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31664448, 29961769, 29661558, 27535533, 27884173, 21937992)
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
Eurofins Ntd Llc (ga)	RCV000081793	SCV000331322	uncertain significance	not provided	2015-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000356764	SCV000648581	benign	Cerebral folate transport deficiency	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313796	SCV000847409	uncertain significance	Inborn genetic diseases	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 Laboratory Services, 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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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 (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive folate receptor deficiency.
Neuberg Centre For Genomic Medicine, NCGM	RCV000356764	SCV002820171	benign	Cerebral folate transport deficiency		criteria provided, single submitter	clinical testing	The splice donor variant c.493+2T>C in FOLR1 (NM_016725.3) has been reported previously as homozygous in three siblings from a consanguineous family with symptoms of cerebral folate transport deficiency (Najmabadi H et al, 2011). It has also been recently reported in trans with a pathogenic variant in an adult patient with stable clinical and MRI features.The c.493+2T>C variant is observed in 430/30,614 (1.4046%) alleles from individuals of South Asian background in gnomAD Exomes and in 13/978 (1.3292%) alleles from individuals of South Asian background in 1000 Genomes. It has been observed in homozygous state in gnomad database in multiple individuals. Considering the high frequency of the variant the possibility that it is disease causing is unlikely and hence the variant has been classified as Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000081793	SCV004137226	benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	FOLR1: BS1, BS2
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000081793	SCV004848158	uncertain significance	not provided	2023-09-12	criteria provided, single submitter	clinical testing	The c.493+2T>C variant in FOLR1 has been reported in at least 3 individuals with neurologic disease (Najmabadi 2011 PMID: 21937992, McCreary 2019 PMID: 31664448, Hiz Kurul 2022 PMID: 34791078). It has also been identified in 1.4% (430/30614) of South Asian chromosomes by gnomAD including 8 homozygotes (http://gnomad.broadinstitute.org, v.2.1.2), which is higher than expected for a disease-causing variant in FOLR1. This variant has also been reported in ClinVar (Variation ID 95750). This variant occurs within the canonical splice site (+/- 1,2) of the last intron of the FOLR1 gene and is predicted to cause altered splicing. In summary, due to the conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Strong, BS1.
OMIM	RCV000356764	SCV000053287	pathogenic	Cerebral folate transport deficiency	2011-09-21	flagged submission	literature only
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	Seizure	2017-08-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925073	SCV004744864	likely benign	FOLR1-related disorder	2019-05-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).