NM_005957.5(MTHFR):c.665C>T (p.Ala222Val) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance; other (3 submissions)
Last evaluated:: Jan 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000153516.41

Allele description

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]

Observations:

253

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Solenopsis invicta isolate HUM03-7 haplotype b1 general protein-9 (GP-9) gene, c...
Solenopsis invicta isolate HUM03-7 haplotype b1 general protein-9 (GP-9) gene, complete cds
gi|264666809|gb|GU086708.1|

Nucleotide
nuclear receptor corepressor 1 isoform 3 [Homo sapiens]
nuclear receptor corepressor 1 isoform 3 [Homo sapiens]
gi|298919181|ref|NP_001177369.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000203040	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	other (Jan 13, 2017)	germline	clinical testing	Citation Link,
SCV000884146	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Nov 29, 2023)	germline	clinical testing	Citation Link,
SCV001147149	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Jan 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000203040

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

other
(Jan 13, 2017)

germline

clinical testing

Citation Link,

SCV000884146

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain significance
(Nov 29, 2023)

germline

clinical testing

Citation Link,

SCV001147149

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(Jan 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	9	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	244	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Eurofins Ntd Llc (ga), SCV000203040.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	244	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		244	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000884146.7

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

Description

The MTHFR c.665C>T; p.Ala222Val variant (rs1801133), also known as C677T or the thermolabile variant, is listed in the ClinVar database (Variation ID: 3520) and is observed in the general population with an overall allele frequency of 30.8% (87,234/282,784 alleles including 15,819 homozygotes) in the Genome Aggregation Database. The thermolabile c.665C>T variant in the homozygous state has been correlated with reduced enzyme activity and increased homocysteine (Frosst 1995). The practice guidelines from The American College of Medical Genetics state that this variant in the heterozygous state is unlikely to be of clinical significance (Hickey 2013); however, a possible effect of this variant when paired with a pathogenic MTHFR variant on the opposite chromosome cannot be excluded. Additionally, the practice guidelines state that an individual who is homozygous for the c.665C>T; p.Ala222Val variant and has elevated homocysteine may be at mildly increased risk for venous thromboembolism and recurrent pregnancy loss (Hickey 2013). The variant is considered a ''susceptibility'' or an ''association'' variant. REFERENCES Frosst P et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111-3. PMID: 7647779. Hickey SE et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. PMID: 23288205.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001147149.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	not provided

Description

MTHFR: PM3, PM2:Supporting

#	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		9	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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