1-11802962-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_005957.5(MTHFR):c.155G>A(p.Arg52Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R52R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.36

Variant links:

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_005957.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 1-11802962-C-T is Pathogenic according to our data. Variant chr1-11802962-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 570071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.155G>A	p.Arg52Gln	missense_variant	Exon 2 of 12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.155G>A	p.Arg52Gln	missense_variant	Exon 2 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251366

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000124

AC:

182

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 52 of the MTHFR protein (p.Arg52Gln). This variant is present in population databases (rs754980119, gnomAD 0.01%). This missense change has been observed in individual(s) with methylenetetrahydrofolate reductase deficiency (PMID: 7726158, 10923034, 12733064, 21778025, 25079578, 25736335). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.167G>A. ClinVar contains an entry for this variant (Variation ID: 570071). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTHFR protein function. Experimental studies have shown that this missense change affects MTHFR function (PMID: 27743313). For these reasons, this variant has been classified as Pathogenic. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with homocystinuria due to MTHFR deficiency (MIM#236250). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant with conflicting in silico predictions, and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated catalytic domain (PMID: 26872964). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been observed in at least ten families with homocystinuria due to MTHFR deficiency (MIM#236250) (ClinVar, HGMD, PMID: 7726158, PMID: 26872964). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant results in a modest reduction in enzyme activity compared to wild type, as previously demonstrated by in vitro functional studies (PMID: 27743313). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 17, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MTHFR c.155G>A (p.Arg52Gln) variant is a missense variant which has been reported in at least five studies in which it is found in at least seven unrelated individuals with homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency in a homozygous or compound heterozygous state (Goyette et al. 1995; Prasad et al. 2011; Tonetti et al. 2013; D'Aco et al. 2014; Huemer et al. 2016). Four of the affected individuals carried loss of function variants as a second variant. The p.Arg52Gln variant was absent from 300 control alleles and is reported at a frequency of 0.000114 in the European (non-Finnish) population of the Genome Aggregation Database. Expression studies in both patient and non-patient fibroblasts demonstrated reduced MTHFR activity compared to wildtype (Goyette et al. 1995; Huemer et al. 2016; Burda et al. 2017). Based on the collective evidence and application of the ACMG criteria, the p.Arg52Gln variant is classified as pathogenic for methylene tetrahydrofolate reductase deficiency. -

Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect

Pathogenic:1

Jan 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Nov 19, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate reduced enzymatic activity, thermo-stable activity, and NADPH binding affinity in patient cells (Goyette et al., 1995; Burda et al., 2015; Burda et al., 2016); This variant is associated with the following publications: (PMID: 25736335, 7726158, 10923034, 26025547, 33089527, 28537576, 32533987, 21778025, 12406076, 12733064, 27743313, 25079578, 34214447) -

Neural tube defects, folate-sensitive

Pathogenic:1

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.;D;.;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.97

.;D;.;D;D;D;D;D

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.5

M;.;.;M;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

N;N;N;N;.;.;.;N

REVEL

Pathogenic

0.76

Sift

Benign

0.24

T;T;T;T;.;.;.;T

Sift4G

Benign

0.43

T;T;T;T;.;.;.;.

Polyphen

0.74

P;.;.;P;.;.;.;.

Vest4

0.68

MVP

0.98

MPC

0.55

ClinPred

0.35

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over