1-236895470-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000254.3(MTR):​c.3518C>T​(p.Pro1173Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,597,024 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1173P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 7.51
Variant links:
Genes affected
MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
Variant 1-236895470-C-T is Pathogenic according to our data. Variant chr1-236895470-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236895470-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTRNM_000254.3 linkc.3518C>T p.Pro1173Leu missense_variant Exon 31 of 33 ENST00000366577.10 NP_000245.2 Q99707-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTRENST00000366577.10 linkc.3518C>T p.Pro1173Leu missense_variant Exon 31 of 33 1 NM_000254.3 ENSP00000355536.5 Q99707-1
MTRENST00000366576.3 linkc.2180C>T p.Pro727Leu missense_variant Exon 18 of 20 1 ENSP00000355535.3 B1ANE3

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000641
AC:
14
AN:
218506
Hom.:
0
AF XY:
0.0000764
AC XY:
9
AN XY:
117860
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000600
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000530
Gnomad NFE exome
AF:
0.000125
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000190
AC:
274
AN:
1444836
Hom.:
0
Cov.:
60
AF XY:
0.000159
AC XY:
114
AN XY:
716936
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000257
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000385
Gnomad4 NFE exome
AF:
0.000242
Gnomad4 OTH exome
AF:
0.0000671
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000165
Hom.:
0
Bravo
AF:
0.0000680
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000413
AC:
5

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblG Pathogenic:6
Jul 01, 2002
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 01, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MTR c.3518C>T (p.Pro1173Leu) results in a non-conservative amino acid change located in the Vitamin B12-dependent methionine synthase, activation domain (IPR004223) 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 6.4e-05 in 218506 control chromosomes. c.3518C>T has been reported in the literature in multiple individuals affected with Methylcobalamin deficiency type cblG (e.g. DeBiase_2020, Watkins_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32533987, 12068375). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 04, 2019
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous and a heterozygous change in patients with methylcobalamin deficiency G (cblG) disorder (PMID: 8968736, 12068375). Functional studies of methionine synthase activity a fibroblast cell line from a patient carrying this variant showed a 30-fold reduction in enzymatic activity relative to controls, in the presence of NADPH (PMID: 9235907). It is present in the heterozygous state in the gnomAD population database at a frequency of .006% (14/243760) and thus is presumed to be rare. The c.3518C>T (p.Pro1173Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3518C>T (p.Pro1173Leu) variant is classified as pathogenic. -

Mar 25, 2021
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1173 of the MTR protein (p.Pro1173Leu). This variant is present in population databases (rs121913578, gnomAD 0.01%). This missense change has been observed in individual(s) with methionine synthase deficiency (cblG) (PMID: 9235907, 12068375, 25526710). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14278). 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 MTR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

not provided Pathogenic:3
Sep 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MTR: PM3:Strong, PM2, PP4:Moderate, PP3, PS3:Supporting -

May 19, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 31, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24664876, 9235907, 33726816, 28666289, 32581362, 8968736, 12068375, 34625984) -

Disorders of Intracellular Cobalamin Metabolism Pathogenic:1Other:1
Jan 10, 2019
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MTR c.3518C>T (p.Pro1173Leu) is a missense variant that has been reported in at least six studies, in which it was identified in a compound heterozygous state in 14 individuals and in a homozygous state in two individuals, all diagnosed with disorders of intracellular cobalamin metabolism (Gulati et al. 1996; Gulati et al. 1997; Watkins et al. 2002; Wong et al. 2015; Alazami et al. 2015; Komulainen-Ebrahim et al. 2017). Watkins et al. (2002) performed haplotype analysis and determined that the c.3518C>T transition in a CpG island has occurred independently on at least two separate genetic backgrounds. Fibroblast cells from a female, homozygous for the p.Pro1173Leu variant and diagnosed with severe macrocytic anemia at three months, showed 9 % methionine synthase activity compared to the reference, the level of MTR protein was also reduced in these cells compared to control. The p.Pro1173Leu variant was absent from 210 control subjects and is reported at a frequency of 0.000349 in the American European population of the Exome Sequencing Project. Based on the collective evidence, the p.Pro1173Leu variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Epilepsy;C3161330:Intellectual disability, profound Pathogenic:1
Dec 01, 2014
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Homocystinuria;C1848580:Decreased methionine synthase activity Pathogenic:1
-
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Inborn genetic diseases Pathogenic:1
Jun 11, 2015
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P1173L alteration is located in exon 33 of the MTR gene (NM_000254). This alteration results from a C to T substitution at nucleotide position 3518, resulting in an amino acid substitution of leucine for proline at position 1173, an amino acid with dissimilar properties. This alteration (HGMD # CM961003) was first reported in a compound heterozygous state with a 3bp in-frame deletion in a cbIG deficiency patient (Gulati et al. (1996) Hum Mol Genet 5, 1859). It is likely a founder mutation among individuals of European ancestry, consistent with the family's reported ancestry (Rutsch F, et al. (2011) J Inherit Metab Dis 34:121-126, Watkins D, et al. (2002) Am J Hum Genet 71:143-153). The c.3518C>T (p.P1173L) alteration in the MTR gene is the most common alteration, observed at a frequency of about 40% (16/38 chromosomes), in patients with cblG deficiency (Watkins D, et al. (2002) Am J Hum Genet 71:143-153). This variant was previously reported in the SNPDatabase as rs121913578. Based on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately 0.03% (4/12,990) total alleles studied. The T-allele was observed in 0.03% (3/8,588) European American alleles and in 0.02% (1/4,402) African American alleles studied. To our knowledge, this alteration has not been previously reported in the 1000 Genome database. This amino acid is completely conserved in available vertebrate species. This variant is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses respectively. Based on the available evidence to date, this variant is classified as a pathogenic mutation. -

MTR-related disorder Pathogenic:1
Dec 17, 2024
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS3_Moderate, PM2, PM3_Very Strong, PP2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.92
.;D;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Pathogenic
4.1
.;H;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-9.7
D;D;D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.88
MVP
0.95
MPC
1.3
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.98
gMVP
0.93

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913578; hg19: chr1-237058770; API