chr1-11800250-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_005957.5(MTHFR):c.548G>A(p.Arg183Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,166 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 (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.26

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 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005957.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 1-11800250-C-T is Pathogenic according to our data. Variant chr1-11800250-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187876.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.548G>A	p.Arg183Gln	missense_variant	Exon 4 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.548G>A	p.Arg183Gln	missense_variant	Exon 4 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000596

AC:

AN:

251492

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:4

Aug 24, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 3 of the MTHFR gene that results in the amino acid substitution of Glutamine for Arginine at codon 183 was detected. The observed variant c.548G>A (p.Arg183Gln) lies in the methylenetetrahydrofolate reductase domain of the MTHFR protein and has previously been reported in homozygous state, in patients affected with homocystinuria (Burda et al. 2015). Functional studies showed that the observed missense caused deleterious loss of MTHFR protein expression and activity (Burda et al. 2017). The variant has a minor allele frequency of 0.02% in the 1000 genomes and 0.006% in gnomAD database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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 183 of the MTHFR protein (p.Arg183Gln). This variant is present in population databases (rs574132670, gnomAD 0.03%). This missense change has been observed in individual(s) with MTHFR deficiency (PMID: 25736335). ClinVar contains an entry for this variant (Variation ID: 187876). Advanced 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 at Invitae 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MTHFR: PM2, PP1:Moderate, PM3:Supporting, PS3:Supporting -

Mar 12, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (residual enzyme activity in fibroblasts ranging from 20-22%) (Burda et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 26872964, 25736335, 27743313) -

Thrombophilia due to thrombin defect

Pathogenic:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.548G>A (p.Arg183Gln) variant in MTHFR gene has been reported in heterozygous/ homozygous states in multiple individuals affected with MTHFR-related disorders (Burda et al., 2015; Capalbo et al., 2019; Froese et al., 2016). Functional studies showed that the variant caused deleterious loss of MTHFR protein expression and activity (Burda et al., 2017). This variant is present with allele frequency of 0.006% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg183Gln in MTHFR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 183 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Neural tube defects, folate-sensitive

Pathogenic:1

Feb 22, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

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

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.4

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

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

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

Vest4

0.92

MutPred

0.83

Loss of ubiquitination at K180 (P = 0.0613);.;.;Loss of ubiquitination at K180 (P = 0.0613);.;Loss of ubiquitination at K180 (P = 0.0613);Loss of ubiquitination at K180 (P = 0.0613);

MVP

1.0

MPC

0.99

ClinPred

0.81

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -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