rs267606886

Variant names:

• chr1-11795114-A-C
• rs267606886
• NM_005957.5:c.1015T>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_005957.5(MTHFR):​c.1015T>G​(p.Trp339Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-11795114-A-C is Pathogenic according to our data. Variant chr1-11795114-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3523.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	c.1015T>G	p.Trp339Gly	missense_variant	Exon 6 of 12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1015T>G	p.Trp339Gly	missense_variant	Exon 6 of 12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:3

Jun 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan with glycine at codon 339 of the MTHFR protein (p.Trp339Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MTHFR protein function (PMID: 27743313). This variant has been observed in individual(s) with MTHFR deficiency (PMID: 9781030, 25736335). ClinVar contains an entry for this variant (Variation ID: 3523). This variant is not present in population databases (ExAC no frequency). -

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MTHFR c.1015T>G (p.Trp339Gly) results in a non-conservative amino acid change located in the FAD-linked oxidoreductase domain (IPR029041) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249772 control chromosomes. c.1015T>G has been reported in the literature in multiple homozygous individuals affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency (e.g. Burda_2015, Kluijtmans_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (e.g. Burda_2015, Kluijtmans_1998). The following publications have been ascertained in the context of this evaluation (PMID: 25736335, 9781030). ClinVar contains an entry for this variant (Variation ID: 3523). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Benign	0.97
DEOGEN2	Uncertain	0.71	D;.;.;D;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.9	M;.;.;M;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;.;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.027	D;T;T;D;.;.;.
Sift4G	Uncertain	0.047	D;T;T;D;.;.;.
Polyphen		0.0060	B;.;.;B;.;.;.
Vest4		0.92
MutPred		0.86		Gain of disorder (P = 0.0019);.;.;Gain of disorder (P = 0.0019);.;Gain of disorder (P = 0.0019);.;
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 22

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606886; hg19: chr1-11855171;