Submissions for variant NM_015506.3(MMACHC):c.440G>C (p.Gly147Ala)

gnomAD frequency: 0.00034  dbSNP: rs140522266

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186028	SCV000238991	pathogenic	not provided	2024-09-28	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000262040	SCV000357927	likely pathogenic	Disorders of Intracellular Cobalamin Metabolism	2017-04-27	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576585	SCV000699400	pathogenic	Cobalamin C disease	2021-08-19	criteria provided, single submitter	clinical testing	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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000576585	SCV000746399	pathogenic	Cobalamin C disease	2017-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576585	SCV000762781	pathogenic	Cobalamin C disease	2025-01-14	criteria provided, single submitter	clinical testing	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). 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) has been performed 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.
Fulgent Genetics, Fulgent Genetics	RCV000576585	SCV000894026	pathogenic	Cobalamin C disease	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000576585	SCV001162908	pathogenic	Cobalamin C disease	2024-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576585	SCV001193790	likely pathogenic	Cobalamin C disease	2019-12-17	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000186028	SCV001248086	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000186028	SCV001713013	likely pathogenic	not provided	2020-04-20	criteria provided, single submitter	clinical testing	PS4_moderate, PM2, PM5, PP3, PP5
Genome-Nilou Lab	RCV000576585	SCV001810504	pathogenic	Cobalamin C disease	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000576585	SCV002023491	likely pathogenic	Cobalamin C disease	2022-11-11	criteria provided, single submitter	clinical testing
DASA	RCV000576585	SCV002061302	pathogenic	Cobalamin C disease	2022-01-05	criteria provided, single submitter	clinical testing	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 (rs140522266– 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.
Genetics and Molecular Pathology, SA Pathology	RCV000576585	SCV002761415	likely pathogenic	Cobalamin C disease	2019-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517827	SCV003675871	pathogenic	Inborn genetic diseases	2022-01-25	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000576585	SCV005398822	pathogenic	Cobalamin C disease	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with methylmalonic aciduria and homocystinuria, cblC type (MIM#277400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (91 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated methylmalonic aciduria and homocystinuria type C family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant hass been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as compound heterozygous or homozygous in individuals with cblC type methylmalonic aciduria and homocystinuria (PMIDs: 16311595, 19370762, 25689098, 26825575, 34356170). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001027895	SCV001190618	pathogenic	Homocystinuria; Methylmalonic aciduria	2019-05-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001273224	SCV001456016	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000186028	SCV001740284	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000186028	SCV001809518	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000186028	SCV001953971	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000262040	SCV003354478	not provided	Disorders of Intracellular Cobalamin Metabolism		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004755795	SCV005364253	pathogenic	MMACHC-related disorder	2024-04-23	no assertion criteria provided	clinical testing	The MMACHC c.440G>C variant is predicted to result in the amino acid substitution p.Gly147Ala. This variant has been reported in individuals with confirmed methylmalonic aciduria, cblC type, without additional genetic information provided (Lerner-Ellis et al. 2006. PubMed ID: 16311595). It has also been reported in the homozygous state or compound heterozygous state with a second pathogenic variant in patients with confirmed methylmalonic aciduria, cblC type. Several of the reported patients, including one homozygote, presented with a later-onset form of disease, suggesting this variant may have a milder effect (Morel et al. 2006. PubMed ID: 16714133; Thauvin-Robinet et al. 2008. PubMed ID: 18245139; Scolamiero et al. 2015. PubMed ID: 25689098; Brooks et al. 2016. PubMed ID: 26825575). An alternative substitution at the same amino acid (p.Gly147Asp) has been reported to be causative for methylmalonic aciduria, cblC type (Lerner-Ellis et al. 2006. PubMed ID: 16311595). This variant is reported in 0.065% of alleles in individuals of Latino descent in gnomAD and interpreted as likely pathogenic or pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/203828). Taken together, this variant is interpreted as pathogenic.