1-11790858-A-G

Variant names:

• chr1-11790858-A-G
• rs786204034
• NM_005957.5:c.1793T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 1333559.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1793T>C	p.Leu598Pro	missense	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1916T>C	p.Leu639Pro	missense	Exon 12 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.1913T>C	p.Leu638Pro	missense	Exon 12 of 12	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1793T>C	p.Leu598Pro	missense	Exon 12 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.1913T>C	p.Leu638Pro	missense	Exon 12 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.1793T>C	p.Leu598Pro	missense	Exon 12 of 12	ENSP00000365777.1

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

Mar 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.66		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204034; hg19: chr1-11850915;