NM_005957.5(MTHFR):c.665C>T (p.Ala222Val) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Feb 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001030751.21

Allele description [Variation Report for NM_005957.5(MTHFR):c.665C>T (p.Ala222Val)]

NM_005957.5(MTHFR):c.665C>T (p.Ala222Val)

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.665C>T (p.Ala222Val)

Other names:

MTHFR, 677C-T, ALA222VAL (rs1801133); C667T

HGVS:

NC_000001.11:g.11796321G>A
NG_013351.1:g.14783C>T
NM_001330358.2:c.788C>T
NM_005957.5:c.665C>TMANE SELECT
NP_001317287.1:p.Ala263Val
NP_005948.3:p.Ala222Val
NP_005948.3:p.Ala222Val
LRG_726t1:c.665C>T
LRG_726:g.14783C>T
LRG_726p1:p.Ala222Val
NC_000001.10:g.11856378G>A
NM_005957.4:c.665C>T
P42898:p.Ala222Val

Protein change:

A222V; ALA222VAL

Links:

Genetic Testing Registry (GTR): GTR000593372; PharmGKB: 827848365; PharmGKB: 827848365PA450428; PharmGKB: 981204929; PharmGKB: 981204929PA449165; PharmGKB: 981220481; PharmGKB: 981220481PA448803; PharmGKB Clinical Annotation: 981204929; PharmGKB Clinical Annotation: 981220481; UniProtKB: P42898#VAR_009528; OMIM: 607093.0003; dbSNP: rs1801133

NCBI 1000 Genomes Browser:

rs1801133

Molecular consequence:

NM_001330358.2:c.788C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.665C>T - 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

alanine--tRNA ligase [Olsenella uli]
alanine--tRNA ligase [Olsenella uli]
gi|503017013|ref|WP_013251989.1|

Protein
Culicicapa ceylonensis voucher 2674 cytochrome b (cytb) gene, partial cds; mitoc...
Culicicapa ceylonensis voucher 2674 cytochrome b (cytb) gene, partial cds; mitochondrial
gi|769471093|gb|KJ702903.1|

Nucleotide
glia-derived nexin isoform a precursor [Homo sapiens]
glia-derived nexin isoform a precursor [Homo sapiens]
gi|24307907|ref|NP_006207.1|

Protein

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
SCV001194043	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 16, 2019)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 7647779, 8837319, 9545406, 11781870, 12560871, 8903338, 9789068, 11929966, 15565101, 17436239, 12356947, 9133512, 12196644, 9798595 Citation Link,
SCV001366606	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423141	Neurology Department, Peking University First Hospital	no assertion criteria provided	Uncertain significance (Apr 23, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001463167	Natera, Inc.	no assertion criteria provided	Benign (Dec 7, 2019)	germline	clinical testing
SCV001733273	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

The incidence of the gene for thermolabile methylene tetrahydrofolate reductase in African Americans.

McAndrew PE, Brandt JT, Pearl DK, Prior TW.

Thromb Res. 1996 Jul 15;83(2):195-8.

PubMed [citation]

PMID:: 8837319

Worldwide distribution of a common methylenetetrahydrofolate reductase mutation.

Schneider JA, Rees DC, Liu YT, Clegg JB.

Am J Hum Genet. 1998 May;62(5):1258-60. No abstract available.

PubMed [citation]

PMID:: 9545406
PMCID:: PMC1377093

See all PubMed Citations (16)

Details of each submission

From Myriad Genetics, Inc., SCV001194043.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

NM_005957.4(MTHFR):c.665C>T(A222V) is a common variant present in approximately 30% of the general population. While many individuals who are homozygous for this variant are asymptomatic, some may have mild MTHFR deficiency associated with increased plasma homocysteine. Sources cited for classification include the following: PMID 7647779, 8837319, 9545406, 11781870, 12560871, 8903338, 9789068, 11929966, 15565101, 17436239, 12356947, 9133512, 12196644 and 9798595. Classification of NM_005957.4(MTHFR):c.665C>T(A222V) is based on the following criteria: This is a well-established variant in the literature that has been observed more frequently in patients with mild MTHFR deficiency than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.

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

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366606.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state.

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

From Neurology Department, Peking University First Hospital, SCV001423141.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Natera, Inc., SCV001463167.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001733273.4

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine