rs121913578

Positions:

chr1-236895470-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_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

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O: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]

MTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MTR. . Gene score misZ 2.0433 (greater than the threshold 3.09). Trascript score misZ 3.2999 (greater than threshold 3.09). GenCC has associacion of gene with methylcobalamin deficiency type cblG.

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/exons	MANE	UniProt
MTR	NM_000254.3 linkuse as main transcript	c.3518C>T	p.Pro1173Leu	missense_variant	31/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10 linkuse as main transcript	c.3518C>T	p.Pro1173Leu	missense_variant	31/33	1	NM_000254.3	P1	Q99707-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152188

Hom.:

Cov.:

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:

AN:

218506

Hom.:

AF XY:

0.0000764

AC XY:

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.:

Cov.:

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:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

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.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblG

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Apr 04, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2002	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2023	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MTR: PM3:Strong, PM2, PP4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -

Disorders of Intracellular Cobalamin Metabolism

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 10, 2019	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Epilepsy;C3161330:Intellectual disability, profound

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

Homocystinuria;C1848580:Decreased methionine synthase activity

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

4.1

.;H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.74

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over