rs121434296

Positions:

chr1-11794766-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_005957.5(MTHFR):c.1129C>T(p.Arg377Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 3.90

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:

MTHFR (HGNC:):

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11794765-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 654511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 1-11794766-G-A is Pathogenic according to our data. Variant chr1-11794766-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3528.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.1129C>T	p.Arg377Cys	missense_variant	7/12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.1129C>T	p.Arg377Cys	missense_variant	7/12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152206

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251484

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000385

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the MTHFR protein (p.Arg377Cys). This variant is present in population databases (rs121434296, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of severe MTHFR deficiency and/or MTHFR deficiency (PMID: 8940272, 12673793, 17409006, 25736335, 26025547, 26872964; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Amish ancestry (PMID: 17409006). This variant is also known as C1141T. ClinVar contains an entry for this variant (Variation ID: 3528). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on MTHFR function (PMID: 10551815, 27743313, 34214447). This variant disrupts the p.Arg377 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10923034, 26025547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 23, 2024	Variant summary: MTHFR c.1129C>T (p.Arg377Cys) results in a non-conservative amino acid change located in the MTHFR, SAM-binding regulatory domain (IPR053806) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251484 control chromosomes (gnomAD). c.1129C>T has been reported in the literature in multiple individuals including homozygotes affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency (examples : Strauss_2007, Gowda_2021, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. In vitro functional assays show reduced activity for the variant (Burda_2017). The following publications have been ascertained in the context of this evaluation (PMID: 17409006, 34347262, 28468868, 27743313). ClinVar contains an entry for this variant (Variation ID: 3528). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 06, 2018	The c.1129C>T; p.Arg377Cys variant has been reported multiple times in the literature. An African-American/Caucasian female with lethargy and failure to thrive at one month of age, and seizures, apnea, and hypotonia at three months of age was reported to be compound heterozygous for this variant as well as p.Leu323Pro (Goyette 1996). A 13-year-old male with developmental delay was reported to be compound heterozygous for the p.Arg377Cys and p.Met338Thr variants (Sibani 2003), and a study of families diagnosed with severe MTHFR deficiency reported two further individuals heterozygous for p.Arg377Cys and either p.His181Asp or p.Cys193Tyr (Tonetti 2003). A study of an Amish community found four children homozygous for the p.Arg377Cys variant, all of whom had slow head growth and arrested development in the first few months of life; while 68 heterozygotes were among 230 healthy individuals in the community, for an estimated population carrier frequency of 30% (Strauss 2007). The four p.Arg377Cys homozygotes all displayed elevated plasma N-homocysteinylated protein, Hcy-thiolactone and total homocysteine concentrations (Jakubowski 2008). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% (identified on 5 out of 126,714 chromosomes) and an East Asian population frequency of zero (out of 18,870 chromosomes), while the Exome Sequencing Project reports the variant frequency as 0.008% (identified on 1 out of 13,005 chromosomes). However, a study of congenital heart disease risk in China identified the p.Arg377Cys variant in a homozygous state in 12 healthy individuals and 27 affected patients among 467 studied Chinese Han individuals, with an allele frequency of over 25% (Zhang 2014). The discrepancy between this report and those of the population databases has not yet been explained. Although these findings are suggestive, based on the available evidence, the clinical significance of the p.Arg377Cys variant cannot be determined with certainty. -

Neural tube defects, folate-sensitive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

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

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.93

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

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

4.0

H;.;.;H;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.9

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

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.95

MVP

0.89

MPC

1.1

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.93

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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