rs118204046

Positions:

chr2-149570119-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_015702.3(MMADHC):c.746A>G(p.Tyr249Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,613,814 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 (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

MMADHC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

PP5

Variant 2-149570119-T-C is Pathogenic according to our data. Variant chr2-149570119-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-149570119-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3 linkuse as main transcript	c.746A>G	p.Tyr249Cys	missense_variant	8/8	ENST00000303319.10	NP_056517.1	Q9H3L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MMADHC	ENST00000303319.10 linkuse as main transcript	c.746A>G	p.Tyr249Cys	missense_variant	8/8	1	NM_015702.3	ENSP00000301920.5	Q9H3L0
MMADHC	ENST00000422782.2 linkuse as main transcript	c.848A>G	p.Tyr283Cys	missense_variant	9/9	5		ENSP00000408331.2	F8WEC0
MMADHC	ENST00000428879.5 linkuse as main transcript	c.746A>G	p.Tyr249Cys	missense_variant	7/7	2		ENSP00000389060.1	Q9H3L0

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251290

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000164

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 25, 2022	The MMADHC c.746A>G variant is classified as Pathogenic (PS4_Moderate, PS3, PM2, PM3, PP3) The MMADHC c.746A>G variant is a single nucleotide change in exon 8/8 of the MMADHC gene, which is predicted to change the amino acid tyrosine at position 249 in the protein to cysteine. The variant has been reported in probands with a clinical presentation of OMIM:277410 ( Detected in at least 4 affected individuals ) (PS4_Moderate). The variant is rare in population databases (PM2). Well-established functional studies show a deleterious effect of this variant (PS3). PubMed: 18385497 - Severely reduced methionine or methylcobalamin synthesis in either cblD-homocystinuria or cblD-combined cells. PMID: 22156578 - Expression studies showed that the c.746A>G;p.(Tyr249Cys) variant was unable to rescue methylcobalamin (MeCbl) synthesi. This variant has been detected in trans with a pathogenic variant c.545C>A;p.(T182N) for this recessive condition (PM3). + 3 homozygous occurrences. Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs118204046) and in the HGMD database: CM081190. It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 763). - Variant detected in an individual with homocystinuria. Variant in trans with c.545C>A;p.(Thr182Asn). - Constructs containing the missense alleles associated with isolated homocystinuria (545C→A, 746A→G, and 776T→C) did not restore methionine or methylcobalamin synthesis in either cblD-homocystinuria or cblD-combined cells, confirming that these mutant alleles cause the homocystinuria phenotype. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.746A>G(p.Tyr249Cys) in MMADHC gene has been reported in homozygous and compound heterozygous state in individuals with cobalamin D deficiency (Coelho D, et al., 2008, Stucki M, et al., 2012, Atkinson C, et al., 2014). This mutation occurs in a region of the MMADHC gene that is highly conserved among species. Experimental studies have shown that this variant causes deficient synthesis of methylcobalamin (Coelho D, et al., 2008, Atkinson C, et al., 2014). The c.746A>G variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance/ Likely Pathogenic/ Pathogenic.The amino acid Tyrosine at position 249 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Tyr249Cys in MMADHC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 249 of the MMADHC protein (p.Tyr249Cys). This variant is present in population databases (rs118204046, gnomAD 0.04%). This missense change has been observed in individual(s) with cobalamin D deficiency (PMID: 18385497, 22156578, 25155779). ClinVar contains an entry for this variant (Variation ID: 763). 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 MMADHC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MMADHC function (PMID: 18385497, 22156578). 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. -

Cobalamin C disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 02, 2022

Variant summary: MMADHC c.746A>G (p.Tyr249Cys) results in a non-conservative amino acid change in 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 7.2e-05 in 251290 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MMADHC causing Methylmalonic Acidemia With Homocystinuria (7.2e-05 vs 0.00079), allowing no conclusion about variant significance. c.746A>G has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia With Homocystinuria, including one heterozygote (Coelho_2008) and 3 homozygotes (Stucki_2012, Atkinson_2014). These data indicate that the variant is very likely to be associated with disease. Two publications have reported experimental evidence evaluating an impact on protein function, where the variant protein was found impacting methylcobalamin synthesis (with 10%-<30% of normal activity) but not adenosylcobalamin synthesis (Coelho_2008, Stucki_2012). One ClinVar submitter has assessed this variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblD TYPE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 03, 2008

- -

See cases

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 22, 2019

ACMG classification criteria: PM2, PP3, PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.1

M;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.5

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.78

MutPred

0.70

.;.;Loss of disorder (P = 0.085);

MVP

0.84

MPC

0.27

ClinPred

0.88

GERP RS

5.0

Varity_R

0.88

gMVP

0.69

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