rs398124292

chr1-45507544-T-TA

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.271dup(p.Arg91LysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V90V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: MMACHC NM_015506.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:44 O:1
• Conservation: PhyloP100: 1.08

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45507544-T-TA is Pathogenic according to our data. Variant chr1-45507544-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 1421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.271dup	p.Arg91LysfsTer14	frameshift_variant	2/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.100dup	p.Arg34LysfsTer14	frameshift_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.271dup	p.Arg91LysfsTer14	frameshift_variant	2/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.100dup	p.Arg34LysfsTer14	frameshift_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00116 AC: 290 AN: 249456 Hom.: 0 AF XY: 0.00126 AC XY: 170 AN XY: 135346

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00104 AC: 1517 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 758 AN XY: 727236

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.000953 AC XY: 71 AN XY: 74466

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00111

EpiCase AF: 0.00251

EpiControl AF: 0.00255

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:44 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Pathogenic:24

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 08, 2013	The Arg91LysfsX14 variant in MMACHC has been identified in homozygosity in 81 individuals and in compound heterozygosity in 86 individuals with methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis 2006, Richard 2009, Liu 2010). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 91 and lead to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 11, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 strong -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 10, 2020	- -
Pathogenic, no assertion criteria provided	research	Neurology Department, Peking University First Hospital	Apr 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_015506.2(MMACHC):c.271dupA(R91Kfs*14) is classified as pathogenic in the context of cblC type methylmalonic aciduria and homocystinuria and may be associated with the early onset form of disease. Sources cited for classification include the following: PMID 19370762. Classification of NM_015506.2(MMACHC):c.271dupA(R91Kfs*14) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.112%). This variant was 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001421 / PMID: 16311595). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 20, 2021	This variant was identified as compound heterozygous with NM_015506.3:c.658_660del._x000D_ Criteria applied: PVS1, PM3_VSTR, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 4). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (314 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants also predicted to result in NMD, have very strong previous evidence for pathogenicity in patients with Methylmalonic acidemia (Decipher, ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in many unrelated individuals with Methylmalonic acidemia (LOVD, ClinVar, PMID: 31279840). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.270_271insA;p.(Arg91Lysfs*14) is a null frameshift variant (NMD) in the MMACHC gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1421; PMID: 16311595; PMID: 19760748; PMID: 20631720; PMID: 24599607; PMID: 25894566) - PS4. The variant is present at low allele frequencies population databases (rs398124292 – gnomAD 0.00008037%; ABraOM 0.003843 frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Feb 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2016	Variant summary: The MMACHC c.271dupA (p.Arg91Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 132/120196 control chromosomes at a frequency of 0.0010982, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant is a well known common disease variant and has been reported in numerous affected individuals in the literature, including individuals carrying the variant in the homozygous and compound heterozygous state (Lerner-Ellis_2006). Supporting the pathogenicity of this variant, incorporation of labelled methyltetrahydrofolate and propionate into cellular macromolecules was significantly affected in patients with homozygous or compound heterozygous c.271dupA (Lerner-Ellis_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg91Lysfs*14) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs543840147, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with early onset cobalamin C deficiency (PMID: 16311595, 19760748, 20631720, 24599607, 25894566). ClinVar contains an entry for this variant (Variation ID: 1421). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 10, 2021	- -

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 28, 2021	PVS1, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2023	PM3_very_strong, PS3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MMACHC: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24599607, 19760748, 25687216, 32164588, 31681265, 24210589, 20631720, 23954310, 23837176, 21228398, 16311595, 25894566, 26979128, 27014578, 29302025, 26990548, 30712249, 29294253, 28835862, 31137025, 28481040, 27252276, 31497484, 31574870, 32071835, 31503356, 30157807, 31998365, 31980526, 31589614, 32943488, 33587123) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2020	This duplication causes a shift in the reading frame and is expected to result in the loss of a functional protein. Experimental evidence has demonstrated a significant reduction in transcript levels in the presence of this variant (PMID: 19370762). This variant has been identified homozygous and compound heterozygous in multiple individuals with clinical features associated with this gene, and has been reported as a common disease causing variant (PMID: 16311595, 19760748, 20631720, 24599607). The frequency of this variant in the general population is consistent with pathogenicity for a recessive disorder (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Disorders of Intracellular Cobalamin Metabolism Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Accounts for approximately 30%-50% of disease alleles in individuals of European ancestry. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 26, 2017	The MMACHC c.271dupA (p.Arg91LysfsTer14) variant, also referred to as c.270_271insA, results in a frameshift variant and is predicted to result in premature termination of the protein. The p.Arg91LysfsTer14 variant is well described in the literature and is reported as the most common pathogenic variant in the MMACHC gene accounting for approximately 40% of disease alleles (Manoli et al. 2016). The variant has been reported in at least 12 studies in which it was found in over 270 individuals with disorders of intracellular cobalamin metabolism, including at least 127 in a homozygous state and 143 in a compound heterozygous state (Lerner-Ellis et al. 2006; Morel et al. 2006; Heil et al. 2007; Nogueira et al. 2008; Lerner-Ellis et al. 2009; Perez et al. 2010; Frattini et al. 2010; Tsai et al. 2011; Komhoff et al. 2103; Gizicki et al. 2014; Fischer et al. 2014; Collison et al. 2015). The variant was absent from 105 controls and is reported at a frequency of 0.00173 in the European American population of the Exome Sequencing Project. Individuals who carry the p.Arg91LysfsTer14 variant in a homozygous state tend to have an earlier age of onset of the condition while the age of onset of disease when carried in the compound heterozygous state varies depending on the second variant (Morel et al. 2006). Functional studies in patient fibroblasts demonstrated that the p.Arg91LysfsTer variant results in significantly lower levels of transcript compared to wild type. Based on the potential impact of frameshift variants and the supporting evidence from the literature, the p.Arg91LysfsTer14 variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

MMACHC-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The MMACHC c.271dupA variant is predicted to result in a frameshift and premature protein termination (p.Arg91Lysfs*14). This variant is one of the most commonly reported pathogenic variants causative for methylmalonic acidemia and homocystinuria, cblC type (Lerner-Ellis et al. 2006. PubMed ID: 16311595; Richard et al. 2009. PubMed ID: 19760748). It has been interpreted as pathogenic by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/1421/). This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Numerous other premature protein termination variants in MMACHC have been reported to be disease-causing (Human Gene Mutation Database). This variant is interpreted as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 05, 2016

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2021

The c.271dupA (p.R91Kfs*14) alteration, located in exon 2 (coding exon 2) of the MMACHC gene, consists of a duplication of A at position 271, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the MMACHC c.271dupA alteration was observed in 0.11% (314/280836) of total alleles studied, with a frequency of 0.28% (29/10356) in the Ashkenazi Jewish subpopulation. This mutation has been reported in the homozygous and compound heterozygous states in multiple unrelated patients with methylmalonic aciduria and homocystinuria, cblC type. It is the most frequently identified MMACHC mutation accounting for 30-50% of alleles and is typically associated with infantile onset disease (Lerner-Ellis, 2006; Richard, 2009; Fischer, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2015

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 06, 2022

ACMG classification criteria: PVS1, PS4, PM3 -

Atypical hemolytic-uremic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 09, 2019

This individual is heterozygous for a pathogenic variant c.271dup in the MMACHC gene. This frameshifting variant is predicted to create a premature stop codon p.(Arg91Lysfs*14) and may result in a null allele due to nonsense-mediated mRNA decay. This variant is one of the most common variants associated with cblC type methylmalonic aciduria and homocystinuria (Lerner-Ellis et al 2006 Nat Genet 38:93-100). This variant is considered to be pathogenic according to the ACMG guidelines. -

Methylmalonic acidemia with homocystinuria cblC Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs398124292; hg19: chr1-45973216;