NM_005957.5(MTHFR):c.1088G>A (p.Arg363His) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 29, 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:: RCV000167609.2

Allele description [Variation Report for NM_005957.5(MTHFR):c.1088G>A (p.Arg363His)]

NM_005957.5(MTHFR):c.1088G>A (p.Arg363His)

Gene:

MTHFR:methylenetetrahydrofolate reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.22

Genomic location:

Preferred name:

NM_005957.5(MTHFR):c.1088G>A (p.Arg363His)

HGVS:

NC_000001.11:g.11794807C>T
NG_013351.1:g.16297G>A
NM_001330358.2:c.1211G>A
NM_005957.5:c.1088G>AMANE SELECT
NP_001317287.1:p.Arg404His
NP_005948.3:p.Arg363His
NP_005948.3:p.Arg363His
LRG_726t1:c.1088G>A
LRG_726:g.16297G>A
LRG_726p1:p.Arg363His
NC_000001.10:g.11854864C>T
NM_005957.4:c.1088G>A
P42898:p.Arg363His

Protein change:

R363H

Links:

UniProtKB: P42898#VAR_074140; dbSNP: rs786204023

NCBI 1000 Genomes Browser:

rs786204023

Molecular consequence:

NM_001330358.2:c.1211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.1088G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Homocystinuria due to methylene tetrahydrofolate reductase deficiency
Synonyms:: HOMOCYSTINURIA DUE TO DEFICIENCY OF N(5,10)-METHYLENETETRAHYDROFOLATE REDUCTASE ACTIVITY; Homocysteinemia due to MTHFR deficiency; Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009353; MedGen: C1856061; Orphanet: 395; OMIM: 236250

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000218490	University Children's Hospital, University of Zurich	no assertion criteria provided (Clinical disease; enzymatic activity/kinetics in patient fibroblasts)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003522798	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25736335, 27743313, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218490

University Children's Hospital, University of Zurich

no assertion criteria provided

(Clinical disease; enzymatic activity/kinetics in patient fibroblasts)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003522798

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 29, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients.

Burda P, Schäfer A, Suormala T, Rummel T, Bürer C, Heuberger D, Frapolli M, Giunta C, Sokolová J, Vlášková H, Kožich V, Koch HG, Fowler B, Froese DS, Baumgartner MR.

Hum Mutat. 2015 Jun;36(6):611-21. doi: 10.1002/humu.22779. Epub 2015 Apr 27.

PubMed [citation]

PMID:: 25736335

Functional characterization of missense mutations in severe methylenetetrahydrofolate reductase deficiency using a human expression system.

Burda P, Suormala T, Heuberger D, Schäfer A, Fowler B, Froese DS, Baumgartner MR.

J Inherit Metab Dis. 2017 Mar;40(2):297-306. doi: 10.1007/s10545-016-9987-0. Epub 2016 Oct 14.

PubMed [citation]

PMID:: 27743313

See all PubMed Citations (3)

Details of each submission

From University Children's Hospital, University of Zurich, SCV000218490.1

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

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

From Invitae, SCV003522798.1

#	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 363 of the MTHFR protein (p.Arg363His). This variant is present in population databases (rs786204023, gnomAD 0.003%). This missense change has been observed in individual(s) with methylenetetrahydrofolate reductase deficiency (PMID: 25736335). ClinVar contains an entry for this variant (Variation ID: 187889). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MTHFR function (PMID: 27743313). 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: Jun 23, 2024

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