NM_005957.5(MTHFR):c.233C>G (p.Ser78Ter) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 16, 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:: RCV001236475.10

Allele description [Variation Report for NM_005957.5(MTHFR):c.233C>G (p.Ser78Ter)]

NM_005957.5(MTHFR):c.233C>G (p.Ser78Ter)

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.233C>G (p.Ser78Ter)

HGVS:

NC_000001.11:g.11802884G>C
NG_008766.1:g.1735G>C
NG_013351.1:g.8220C>G
NM_001330358.2:c.356C>G
NM_005957.5:c.233C>GMANE SELECT
NP_001317287.1:p.Ser119Ter
NP_005948.3:p.Ser78Ter
LRG_726t1:c.233C>G
LRG_726:g.8220C>G
NC_000001.10:g.11862941G>C
NM_005957.4:c.233C>G

Protein change:

S119*

Links:

dbSNP: rs776969786

NCBI 1000 Genomes Browser:

rs776969786

Molecular consequence:

NM_001330358.2:c.356C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_005957.5:c.233C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001409199	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12733064, 20356773, 25736335, 28492532
SCV002094652	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 26, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001409199

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 16, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002094652

Natera, Inc.

no assertion criteria provided

Pathogenic
(Mar 26, 2020)

germline

clinical testing

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

Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency.

Tonetti C, Saudubray JM, Echenne B, Landrieu P, Giraudier S, Zittoun J.

Eur J Pediatr. 2003 Jul;162(7-8):466-475. doi: 10.1007/s00431-003-1196-9. Epub 2003 May 6.

PubMed [citation]

PMID:: 12733064

Life-threatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: characterization of two novel mutations in compound heterozygous patients.

Forges T, Chery C, Audonnet S, Feillet F, Gueant JL.

Mol Genet Metab. 2010 Jun;100(2):143-8. doi: 10.1016/j.ymgme.2010.03.002. Epub 2010 Mar 6.

PubMed [citation]

PMID:: 20356773

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001409199.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 801438). This premature translational stop signal has been observed in individual(s) with MTHFR deficiency (PMID: 12733064, 20356773). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser78*) in the MTHFR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTHFR are known to be pathogenic (PMID: 25736335).

#	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., SCV002094652.1

#	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 13, 2024

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