1-45508806-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_015506.3(MMACHC):āc.440G>Cā(p.Gly147Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G147D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015506.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.440G>C | p.Gly147Ala | missense_variant | 4/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.269G>C | p.Gly90Ala | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.440G>C | p.Gly147Ala | missense_variant | 4/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.269G>C | p.Gly90Ala | missense_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000334 AC: 83AN: 248850Hom.: 0 AF XY: 0.000341 AC XY: 46AN XY: 135014
GnomAD4 exome AF: 0.000330 AC: 482AN: 1461678Hom.: 0 Cov.: 32 AF XY: 0.000311 AC XY: 226AN XY: 727128
GnomAD4 genome AF: 0.000322 AC: 49AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74464
ClinVar
Submissions by phenotype
Cobalamin C disease Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 17, 2019 | NM_015506.2(MMACHC):c.440G>C(G147A) is classified as likely pathogenic in the context of methylmalonic aciduria and homocystinuria, cblC type. Sources cited for classification include the following: PMID 26825575, 19370762 and 25689098. Classification of NM_015506.2(MMACHC):c.440G>C(G147A) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.440G>C;p.(Gly147Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 203828; PMID: 19370762; 25689098; 26825575) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (MMACHC) - PM1. The variant is present at low allele frequencies population databases (rs140522266ā gnomAD 0.0003220%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly147Ala) was detected in trans with a pathogenic variant (PMID: 25398587; 19370762; 11261516) - PM3_strong. Pathogenic missense variant in this residue have been reported (ClinVar ID: 203829) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 147 of the MMACHC protein (p.Gly147Ala). This variant is present in population databases (rs140522266, gnomAD 0.06%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria, generally with mild or late-onset disease (PMID: 19370762, 25689098, 26825575). 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: 203828). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. This variant disrupts the p.Gly147 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19370762, 19700356). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 30, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 19, 2021 | Variant summary: MMACHC c.440G>C (p.Gly147Ala) 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 0.00033 in 249064 control chromosomes (gnomAD and publication data). This frequency is lower than the maximum expected for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (0.00033 vs 0.0031), allowing no conclusion about variant significance. The variant, c.440G>C, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria, e.g. Lerner-Ellis_2006, Thauvin-Robinet_2008, Lerner-Ellis_2009, Scolamiero_2015). 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. Another missense change affecting the same residue (Gly147Asp) is a known pathogenic variant, suggesting that Gly147 is critical for protein function. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2023 | 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: 25398587, 19370762, 11261516, 16311595, 21748409, 16714133, 17853453, 25689098, 34426522, 31589614, 33848968, 34356170, 32683363, 26825575, 31980526) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 20, 2020 | PS4_moderate, PM2, PM5, PP3, PP5 - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2017 | - - |
Disorders of Intracellular Cobalamin Metabolism Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The MMACHC c.440G>C (p.Gly147Ala) missense variant has been reported in five studies in which it is found in at least five individuals with the cblC type of disorders of intracellular cobalamin metabolism, including in two in a homozygous state and in three in a compound heterozygous state (Lerner-Ellis et al. 2006; Morel et al. 2006; Lerner-Ellis et al. 2009; Yamamoto et al. 2015; Brookes et al. 2016). The variant was also found in one asymptomatic individual identified through newborn screening (Scolamiero et al. 2015). The p.Gly147Ala variant was absent from 155 control samples but is reported at a frequency of 0.00073 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence from the literature the p.Gly147Ala variant is classified as likely pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2022 | The c.440G>C (p.G147A) alteration is located in exon 4 (coding exon 4) of the MMACHC gene. This alteration results from a G to C substitution at nucleotide position 440, causing the glycine (G) at amino acid position 147 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.03% (91/280240) total alleles studied. The highest observed frequency was 0.07% (23/35270) of Latino alleles. This alteration was detected in the homozygous state and in the compound heterozygous state with other MMACHC alterations in multiple individuals with clinical and biochemical features consistent with methylmalonic aciduria and homocystinuria, cblC type (Powers, 2001; Morel, 2005; Scolamiero, 2015; Lerner-Ellis, 2009; Lerner-Ellis, 2006; Valentino, 2021; Brooks, 2016; Yamamoto, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Methylmalonic acidemia with homocystinuria cblC Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Homocystinuria;C1855119:Methylmalonic aciduria Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 20, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at