1-45508806-G-C

Position:

chr1-45508806-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_015506.3(MMACHC):c.440G>C(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G147D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 9.36

Variant links:

Genes affected

MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

MMACHC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_015506.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45508806-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 1-45508806-G-C is Pathogenic according to our data. Variant chr1-45508806-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45508806-G-C is described in Lovd as [Pathogenic]. Variant chr1-45508806-G-C is described in Lovd as [Likely_pathogenic]. Variant chr1-45508806-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3 linkuse as main transcript	c.440G>C	p.Gly147Ala	missense_variant	4/4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 linkuse as main transcript	c.269G>C	p.Gly90Ala	missense_variant	4/4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 linkuse as main transcript	c.440G>C	p.Gly147Ala	missense_variant	4/4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
MMACHC	ENST00000616135.1 linkuse as main transcript	c.269G>C	p.Gly90Ala	missense_variant	4/5	2		ENSP00000478859.1		A0A0C4DGU2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000334

AC:

AN:

248850

Hom.:

AF XY:

0.000341

AC XY:

AN XY:

135014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000639

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000330

AC:

482

AN:

1461678

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000393

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000322

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000477

AC:

ExAC

AF:

0.000430

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.00101

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cobalamin C disease

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
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 (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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 30, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	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 -

not provided

Pathogenic:6

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	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2024	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) -
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 -

Disorders of Intracellular Cobalamin Metabolism

Pathogenic:1Other:1

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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

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. -

MMACHC-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2024

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. -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.2

D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.017

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.96

D;.

Vest4

0.80

MVP

0.98

MPC

0.051

ClinPred

0.43

GERP RS

5.6

Varity_R

0.91

gMVP

0.96

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