rs118204046
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
MMADHC
NM_015702.3 missense
NM_015702.3 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 4.03
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 763.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=3}. Variant chr2-149570119-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMADHC | NM_015702.3 | c.746A>G | p.Tyr249Cys | missense_variant | 8/8 | ENST00000303319.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMADHC | ENST00000303319.10 | c.746A>G | p.Tyr249Cys | missense_variant | 8/8 | 1 | NM_015702.3 | P1 | |
MMADHC | ENST00000422782.2 | c.848A>G | p.Tyr283Cys | missense_variant | 9/9 | 5 | |||
MMADHC | ENST00000428879.5 | c.746A>G | p.Tyr249Cys | missense_variant | 7/7 | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251290Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135848
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GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461616Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39AN XY: 727106
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74348
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Methylmalonic aciduria and homocystinuria type cblD Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
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. - |
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, cblD type, variant 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 03, 2008 | - - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 22, 2019 | ACMG classification criteria: PM2, PP3, PP5 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
0.70
.;.;Loss of disorder (P = 0.085);
MVP
MPC
0.27
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at