NM_005957.5(MTHFR):c.2T>A (p.Met1Lys) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 13, 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:: RCV003093571.2

Allele description [Variation Report for NM_005957.5(MTHFR):c.2T>A (p.Met1Lys)]

NM_005957.5(MTHFR):c.2T>A (p.Met1Lys)

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.2T>A (p.Met1Lys)

HGVS:

NC_000001.11:g.11803115A>T
NG_008766.2:g.1926A>T
NG_013351.1:g.7989T>A
NG_089370.1:g.469A>T
NM_001330358.2:c.125T>A
NM_001410750.1:c.122T>A
NM_005957.5:c.2T>AMANE SELECT
NP_001317287.1:p.Met42Lys
NP_001397679.1:p.Met41Lys
NP_005948.3:p.Met1Lys
NP_005948.3:p.Met1Lys
LRG_726t1:c.2T>A
LRG_726:g.7989T>A
LRG_726p1:p.Met1Lys
NC_000001.10:g.11863172A>T
NG_008766.1:g.1966A>T
NM_005957.4:c.2T>A

Protein change:

M1K

Molecular consequence:

NM_005957.5:c.2T>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001330358.2:c.125T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001410750.1:c.122T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.2T>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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003471941	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25736335, 28241805, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003471941

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 13, 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

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

Rapidly progressive psychotic symptoms triggered by infection in a patient with methylenetetrahydrofolate reductase deficiency: a case report.

Iida S, Nakamura M, Asayama S, Kunieda T, Kaneko S, Osaka H, Kusaka H.

BMC Neurol. 2017 Feb 28;17(1):47. doi: 10.1186/s12883-017-0827-0.

PubMed [citation]

PMID:: 28241805
PMCID:: PMC5330085

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003471941.2

#	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 affects the initiator methionine of the MTHFR mRNA. The next in-frame methionine is located at codon 49. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MTHFR-related conditions. This variant disrupts a region of the MTHFR protein in which other variant(s) (p.Arg46Gln) have been determined to be pathogenic (PMID: 25736335, 28241805). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

ClinVar

Relating variation to medicine