NM_005957.5(MTHFR):c.470G>A (p.Arg157Gln) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 7, 2023
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:: RCV001382824.7

Allele description [Variation Report for NM_005957.5(MTHFR):c.470G>A (p.Arg157Gln)]

NM_005957.5(MTHFR):c.470G>A (p.Arg157Gln)

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.470G>A (p.Arg157Gln)

Other names:

R158Q

HGVS:

NC_000001.11:g.11801166C>T
NG_008766.1:g.17C>T
NG_013351.1:g.9938G>A
NM_001330358.2:c.593G>A
NM_005957.5:c.470G>AMANE SELECT
NP_001317287.1:p.Arg198Gln
NP_005948.3:p.Arg157Gln
LRG_726:g.9938G>A
NC_000001.10:g.11861223C>T
NM_005957.4:c.470G>A
P42898:p.Arg157Gln

Protein change:

R157Q; ARG158GLN

Links:

UniProtKB: P42898#VAR_004320; OMIM: 607093.0002; dbSNP: rs121434295

NCBI 1000 Genomes Browser:

rs121434295

Molecular consequence:

NM_001330358.2:c.593G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.470G>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

Recent activity

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Microbacterium sp. MOLA 56 partial 16S rRNA gene, culture collection MOLA:56
Microbacterium sp. MOLA 56 partial 16S rRNA gene, culture collection MOLA:56
gi|187319395|emb|AM990831.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023859	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 1994)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001581759	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 7, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27743313, 7920641, 10679944, 25736335, 28492532
SCV002094648	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 20, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000023859

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 1994)

germline

literature only

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

SCV001581759

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 7, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002094648

Natera, Inc.

no assertion criteria provided

Pathogenic
(Jan 20, 2020)

germline

clinical testing

Help

Summary from all submissions

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

Citations

PubMed

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

Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification.

Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R.

Nat Genet. 1994 Jun;7(2):195-200. Erratum in: Nat Genet. 1994 Aug;7(4):551..

PubMed [citation]

PMID:: 7920641

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000023859.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with homocystinuria due to MTHFR deficiency (236250), Goyette et al. (1994) demonstrated a G-to-A transition at nucleotide 482 that converted codon 158 from arginine to glutamine. The substitution created a PstI site that was used to verify the substitution and to identify a second patient with this change. The SSCP analysis and the restriction digestion pattern were consistent with a heterozygous state for both patients. In the family of the first patient, the symptomatic brother and the mother carried the mutation, whereas the father was negative. In the second family, the mother was also shown to be a carrier, while the father and an unaffected brother were negative. The clinical picture in these 2 families was that of a milder disorder. The presence of a missense mutation, in conjunction with an allele that produced mRNA, was considered consistent with the low, but detectable, levels of enzyme activity (approximately 10% of controls) as well as with the late onset of the disorder. One brother was still asymptomatic at 37 years of age, although his brother presented with neurologic symptoms at 15 years of age.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001581759.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTHFR protein function. Experimental studies have shown that this missense change affects MTHFR function (PMID: 27743313). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3519). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 157 of the MTHFR protein (p.Arg157Gln). This variant is present in population databases (rs121434295, gnomAD 0.01%). This missense change has been observed in individual(s) with MTHFR deficiency (PMID: 7920641, 10679944, 25736335). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 482G>A.

#	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

From Natera, Inc., SCV002094648.1

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

#	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: Oct 26, 2024

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