1-11790858-A-G

Position:

• chr1-11790858-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_005957.5(MTHFR):​c.1793T>C​(p.Leu598Pro) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L598R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.81

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11790858-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333559.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1793T>C	p.Leu598Pro	missense_variant	12/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1793T>C	p.Leu598Pro	missense_variant	12/12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2022	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 598 of the MTHFR protein (p.Leu598Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe methylenetetrahydrofolate reductase deficiency (PMID: 25736335). ClinVar contains an entry for this variant (Variation ID: 187902). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MTHFR function (PMID: 25736335). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	clinical testing	University Children's Hospital, University of Zurich	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;.;.;D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Pathogenic	3.6	H;.;.;H;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;.;.
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.96
MutPred		0.66		Gain of disorder (P = 0.0102);.;.;Gain of disorder (P = 0.0102);.;.;
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.96

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

Other links and lift over

dbSNP: rs786204034; hg19: chr1-11850915;