1-45508329-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015506.3(MMACHC):c.394C>T(p.Arg132Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,064 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: MMACHC NM_015506.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 1.55

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 65 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45508329-C-T is Pathogenic according to our data. Variant chr1-45508329-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45508329-C-T is described in Lovd as [Pathogenic]. Variant chr1-45508329-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.394C>T	p.Arg132Ter	stop_gained	3/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.223C>T	p.Arg75Ter	stop_gained	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.394C>T	p.Arg132Ter	stop_gained	3/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.223C>T	p.Arg75Ter	stop_gained	3/5	2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000962 AC: 24 AN: 249398 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.0000743 AC XY: 54 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74350

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000993 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Pathogenic:17

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained c.394C>T (p.Arg132Ter) variant in MMACHC gene has been reported previously in homozygous and compound heterozygous state in patients affected with Methylmalonic aciduria and homocystinuria, cblC type (Morel, Chantal F et al.,2006). This variant is reported with the allele frequency 0.009% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in MMACHC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. The observed variant is also detected in the spouse. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Nonsense variant c.394C>T in Exon 3 of the MMACHC gene that results in the amino acid substitution p.Arg132* was identified. The observed variant has a maximum allele frequency of 0.00010/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (ClinVar ID: 1423). This variant has previously been reported for cblC type of methylmalonic aciduria and homocystinuria. Functional assays in patient cell lines indicate that the p.Arg132Ter variant may result in the production of a truncated protein product with residual function (Richard E et al., 2009 and Lerner-Ellis JP et al., 2009). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Program, Stanford Medicine	Mar 04, 2021	The p.Arg132* variant in the MMACHC gene has been previously reported in the homozygous or compound heterozygous state in at least 35 individuals with cobalamin C deficiency (Lerner-Ellis et al., 2006; Nogueira et al., 2008; Lerner-Ellis et al., 2009; Ricci et al., 2020). In one affected cohort, the p.Arg132* variant accounted for 20% of the pathogenic alleles identified and was associated with later onset of disease (Lerner-Ellis et al., 2009). This variant has also been identified in 22/30,600 (0.07%) South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg132* variant leads to a premature stop codon in exon 3 of 4 coding exons, and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Homozygous or compound heterozygous loss of function is an established mechanism of disease for the MMACHC gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg132* variant as pathogenic for autosomal recessive cobalamin C deficiency based on the information above. [ACMG evidence codes used: PVS1; PM3_Very Strong; PM2] -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
Pathogenic, no assertion criteria provided	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jul 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000962, PM2). The variant was observed in trans with a pathogenic variant (NM_015506.2:c.609G>Ap) as compound heterozygous (3billion dataset, PM3). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000001423.16). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Arg132*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 151 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs121918241, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C (cblC) type (PMID: 16311595, 19760748, 20631720, 24577983, 25511120, 26149271, 26563984). 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: 1423). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 02, 2016	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2020	Variant summary: MMACHC c.394C>T (p.Arg132X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 9.6e-05 in 249398 control chromosomes. c.394C>T has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (example, Lerner-Ellis_2009). These data indicate that the variant is very likely to be associated with disease. Eight 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 02, 2020	The MMACHC c.394C>T (p.Arg132Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg132Ter variant is found in at least 57 individuals with the cblC type of methylmalonic aciduria and homocystinuria, the most common inborn error of cobalamin metabolism, including in a homozygous state in at least 31 individuals and in a compound heterozygous state in 26 individuals (Lerner-Ellis et al. 2006; Richard et al. 2009; Lerner-Ellis et al. 2009; Liu et al. 2010; Kılıç et al. 2013). Additionally, this variant has been identified in 20% of disease alleles in individuals from India, Pakistan, and Middle East, and in 5.7% of disease alleles in Chinese population (Lerner-Ellis et al. 2006; Lerner-Ellis et al. 2009; Liu et al. 2010). The p.Arg132Ter variant is associated with late onset disease characterized by acute neurological deterioration without systemic symptoms (Lerner-Ellis et al. 2006). The p.Arg132Ter variant was absent from 155 control subjects (Lerner-Ellis et al. 2006; Lerner-Ellis et al. 2009) but is reported at a frequency of 0.000719 in the South Asian population of the Genome Aggregation Database. Functional assays in patient cell lines indicate that the p.Arg132Ter variant may result in the production of a truncated protein product with residual function (Lerner-Ellis et al. 2009). Furthermore, patient skin fibroblasts do not show an increase in reactive oxygen species levels compared to control cells, however, there was an increase in basal level of apoptosis (Richard et al. 2009). Based on the collective evidence and application of the ACMG criteria, the p.Arg132Ter variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	Reported that many individuals with the R132X variant are of Middle Eastern origin (Lerner-Ellis et al., 2006, Lerner-Ellis et al., 2009); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 151 amino acids are lost; This variant is associated with the following publications: (PMID: 27252276, 27324188, 27629047, 27905001, 17431913, 24577983, 20631720, 25511120, 25525159, 26563984, 26149271, 19760748, 16311595, 27591164, 28218226, 29374341, 28693988, 19370762, 16714133, 23891399, 29581464, 29961769, 30712249, 31203424, 31697851, 31503356, 30157807, 29731766, 31589614, 33083013, 32943488, 32901917) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 08, 2022	PM2, PM3, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -

cblC type of combined methylmalonic aciduria and homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

-

- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

curation

SingHealth Duke-NUS Institute of Precision Medicine

Jun 07, 2017

- -

Abnormality of metabolism/homeostasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Methylmalonic acidemia with homocystinuria cblC Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Disorders of Intracellular Cobalamin Metabolism Other:1

not provided, no classification provided

literature only

GeneReviews

-

Common in people of Indian and Middle Eastern ancestry associated with a late-onset phenotype -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.76	D
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		5.8

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

Other links and lift over

dbSNP: rs121918241; hg19: chr1-45974001;