chr1-11795158-T-C

Variant names:

• chr1-11795158-T-C
• rs267606887
• NM_005957.5:c.971A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_005957.5(MTHFR):​c.971A>G​(p.Asn324Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,322 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N324N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.43
• Publications: 6 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: Pathogenic. The variant received 16 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, 3 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-11795158-T-C is Pathogenic according to our data. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11795158-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 3522.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.971A>G	p.Asn324Ser	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.971A>G	p.Asn324Ser	missense_variant	Exon 6 of 12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461322 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:4

Nov 22, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MTHFR c.971A>G (p.Asn324Ser) results in a conservative amino acid change located in the Methylenetetrahydrofolate reductase domain (IPR003171) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250828 control chromosomes (gnomAD). c.971A>G has been reported in the literature in at least one homozygous individual affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency (Kluijtmans_1998). These data indicate that the variant may be associated with disease. Publications report experimental evidence evaluating an impact on protein function and this variant showed decreased enzyme activity in vitro and in cultured fibroblasts (Kluijtmans_1998, Sibani_2003, Burda_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27743313, 9781030, 12673793, 34214447). ClinVar contains an entry for this variant (Variation ID: 3522). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 324 of the MTHFR protein (p.Asn324Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with methylenetetrahydrofolate reductase deficiency (PMID: 9781030). This variant is also known as A983G. ClinVar contains an entry for this variant (Variation ID: 3522). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MTHFR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MTHFR function (PMID: 12673793, 27743313, 34214447). 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. -

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace asparagine with serine at codon 324 of the MTHFR protein, p.(Asn324Ser). The asparagine residue is evolutionary invariant (100 vertebrates, UCSC), and located in the catalytic domain. There is a small physicochemical difference between asparagine and serine. The variant is absent in a large population cohort (gnomAD v2.1), and has been reported in the homozygous state in at least one case with a biochemically established diagnosis of homocystinuria due to methylenetetrahydrofolate reductase deficiency (PMID: 9781030). In vitro enzymatic assays of the variant demonstrated decreased enzyme activity (further reduced when common polymorphism rs1801133 was in cis), and showed responsiveness to flavin adenine dinucleotide (PMID: 12673793). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PS3_Supporting, PM3_Supporting, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H;.;.;H;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;.
Polyphen		0.98	D;.;.;D;.;.;.
Vest4		0.98
MutPred		0.99		Gain of disorder (P = 0.1833);.;.;Gain of disorder (P = 0.1833);.;Gain of disorder (P = 0.1833);.;
MVP		0.98
MPC		0.71
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.85
Mutation Taster		=0/100	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: rs267606887; hg19: chr1-11855215;