NM_016729.3(FOLR1):c.374G>A (p.Arg125His) AND Cerebral folate transport deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002004355.5

Allele description [Variation Report for NM_016729.3(FOLR1):c.374G>A (p.Arg125His)]

NM_016729.3(FOLR1):c.374G>A (p.Arg125His)

Gene:

FOLR1:folate receptor alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_016729.3(FOLR1):c.374G>A (p.Arg125His)

HGVS:

NC_000011.10:g.72195628G>A
NG_015863.1:g.11071G>A
NM_000802.3:c.374G>A
NM_016724.3:c.374G>A
NM_016725.3:c.374G>A
NM_016729.3:c.374G>AMANE SELECT
NP_000793.1:p.Arg125His
NP_057936.1:p.Arg125His
NP_057937.1:p.Arg125His
NP_057941.1:p.Arg125His
NC_000011.9:g.71906672G>A

Protein change:

R125H

Links:

dbSNP: rs1202769307

NCBI 1000 Genomes Browser:

rs1202769307

Molecular consequence:

NM_000802.3:c.374G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016724.3:c.374G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016725.3:c.374G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016729.3:c.374G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cerebral folate transport deficiency
Synonyms:: Neurodegeneration due to cerebral folate transport deficiency; Cerebral folate deficiency syndrome; FOLATE RECEPTOR DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013110; MedGen: C2751584; Orphanet: 217382; OMIM: 613068

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002290658	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 20, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24091540, 27328863, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002290658

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 20, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood.

Ohba C, Osaka H, Iai M, Yamashita S, Suzuki Y, Aida N, Shimozawa N, Takamura A, Doi H, Tomita-Katsumoto A, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Eto Y, Tanaka F, Matsumoto N, Saitsu H.

Neurogenetics. 2013 Nov;14(3-4):225-32. doi: 10.1007/s10048-013-0375-8. Epub 2013 Oct 4.

PubMed [citation]

PMID:: 24091540

Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation.

Delmelle F, Thöny B, Clapuyt P, Blau N, Nassogne MC.

Eur J Paediatr Neurol. 2016 Sep;20(5):709-13. doi: 10.1016/j.ejpn.2016.05.021. Epub 2016 Jun 13.

PubMed [citation]

PMID:: 27328863

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002290658.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 125 of the FOLR1 protein (p.Arg125His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FOLR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg125 amino acid residue in FOLR1. Other variant(s) that disrupt this residue have been observed in individuals with FOLR1-related conditions (PMID: 24091540, 27328863), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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