Menu
GeneBe

rs1801133

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP3BP4_StrongBA1

The NM_005957.5(MTHFR):c.665C>T(p.Ala222Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.275 in 151970 control chromosomes in the gnomAD Genomes database, including 6918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. A222A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 6918 hom., cov: 32)
Exomes 𝑓: 0.31 ( 14637 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

8
6
3

Clinical Significance

drug response reviewed by expert panel P:3U:5B:10O:3

Conservation

PhyloP100: 9.14

Links

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_005957.5
PP3
?
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0016527474).
BA1
?
GnomAd highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTHFRNM_005957.5 linkuse as main transcriptc.665C>T p.Ala222Val missense_variant 5/12 ENST00000376590.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFRENST00000376590.9 linkuse as main transcriptc.665C>T p.Ala222Val missense_variant 5/121 NM_005957.5 A1P42898-1

Frequencies

GnomAD3 genomes
AF:
0.275
AC:
41856
AN:
151970
Hom.:
6918
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.112
Gnomad AMI
AF:
0.484
Gnomad AMR
AF:
0.444
Gnomad ASJ
AF:
0.461
Gnomad EAS
AF:
0.302
Gnomad SAS
AF:
0.147
Gnomad FIN
AF:
0.235
Gnomad MID
AF:
0.297
Gnomad NFE
AF:
0.337
Gnomad OTH
AF:
0.300
GnomAD3 exomes
AF:
0.315
AC:
79177
AN:
251468
Hom.:
14637
AF XY:
0.309
AC XY:
41934
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.108
Gnomad AMR exome
AF:
0.503
Gnomad ASJ exome
AF:
0.457
Gnomad EAS exome
AF:
0.290
Gnomad SAS exome
AF:
0.145
Gnomad FIN exome
AF:
0.231
Gnomad NFE exome
AF:
0.340
Gnomad OTH exome
AF:
0.330
GnomAD4 exome
AF:
0.323
AC:
471698
AN:
1461758
Hom.:
80805
AF XY:
0.318
AC XY:
231451
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.106
Gnomad4 AMR exome
AF:
0.489
Gnomad4 ASJ exome
AF:
0.460
Gnomad4 EAS exome
AF:
0.355
Gnomad4 SAS exome
AF:
0.149
Gnomad4 FIN exome
AF:
0.233
Gnomad4 NFE exome
AF:
0.337
Gnomad4 OTH exome
AF:
0.308
Alfa
AF:
0.337
Hom.:
23149
Bravo
AF:
0.291
TwinsUK
AF:
0.330
AC:
1224
ALSPAC
AF:
0.334
AC:
1288
ESP6500AA
AF:
0.122
AC:
536
ESP6500EA
AF:
0.347
AC:
2983
ExAC
AF:
0.304
AC:
36865
Asia WGS
AF:
0.190
AC:
662
AN:
3478

ClinVar

Significance: drug response
Submissions summary: Pathogenic:3Uncertain:5Benign:10Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2Uncertain:1Benign:2
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 07, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 17, 2019This 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. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 16, 2019NM_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. -
Uncertain significance, no assertion criteria providedresearchNeurology Department, Peking University First HospitalApr 23, 2020- -
Benign, criteria provided, single submitterclinical testingInvitaeNov 04, 2022- -
not specified Benign:4
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 25, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided Uncertain:1Benign:1Other:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023Criteria applied: BS1, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 06, 2022The 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. 10, 111–113. Hickey SE et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 2013; 15(2):153-156. -
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 13, 2017- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
MTHFR THERMOLABILE POLYMORPHISM Pathogenic:1Benign:1
Benign, no assertion criteria providedliterature onlyOMIMSep 29, 2023- -
Pathogenic, no assertion criteria providedclinical testingFirmaLab, FirmaLab-- -
Neural tube defects, folate-sensitive Benign:2
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely benign, no assertion criteria providedreference populationiDNA Genomics-- -
Stroke Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterJan 06, 2022ACMG categories: PS3,PS4,PM1,BA1 -
Gastrointestinal stroma tumor Uncertain:1
Uncertain significance, no assertion criteria providedcase-controlDepartment of Pharmacy and Biotechnology, University of Bologna-- -
Thrombophilia due to thrombin defect Uncertain:1
Uncertain significance, no assertion criteria providedcurationDepartment Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos UniversityDec 30, 2017- -
methotrexate response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity
Neoplasm of stomach Other:1
not provided, no assertion providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Pathogenic
27
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;.;.;D;.;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.98
D
MetaRNN
Benign
0.0017
T;T;T;T;T;T;T
MetaSVM
Benign
-1.5
T
MutationAssessor
Pathogenic
3.0
M;.;.;M;.;.;.
MutationTaster
Benign
8.6e-8
P;P;P;P
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.8
D;D;D;D;.;.;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0020
D;D;D;D;.;.;.
Sift4G
Uncertain
0.053
T;D;D;T;.;.;.
Polyphen
1.0
D;.;.;D;.;.;.
Vest4
0.47
MPC
0.93
ClinPred
0.020
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1801133; hg19: chr1-11856378; COSMIC: COSV64876755; COSMIC: COSV64876755;