1-45509021-CAGA-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM4_SupportingPP5_Very_Strong

The NM_015506.3(MMACHC):c.658_660delAAG(p.Lys220del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 8.76

Publications

31 publications found

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 Gene-Disease associations (from GenCC):

methylmalonic aciduria and homocystinuria type cblC
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

MMACHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_015506.3

PM4

Nonframeshift variant in NON repetitive region in NM_015506.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-45509021-CAGA-C is Pathogenic according to our data. Variant chr1-45509021-CAGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 95707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.658_660delAAG	p.Lys220del	conservative_inframe_deletion	Exon 4 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
MMACHC	NM_001330540.2 link	c.487_489delAAG	p.Lys163del	conservative_inframe_deletion	Exon 4 of 4		NP_001317469.1	Q9Y4U1A0A0C4DGU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 link	c.658_660delAAG	p.Lys220del	conservative_inframe_deletion	Exon 4 of 4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
MMACHC	ENST00000616135.1 link	c.487_489delAAG	p.Lys163del	conservative_inframe_deletion	Exon 4 of 5	2		ENSP00000478859.1		A0A0C4DGU2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

249382

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461864

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000140

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cobalamin C disease

Pathogenic:13

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MMACHC c.658_660delAAG (p.Lys220del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4.7e-05 in 276980 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (4.7e-05 vs 0.0031), allowing no conclusion about variant significance. The variant, c.658_660delAAG has been reported in the literature in multiple Chinese individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (e.g. Liu 2010, Weisfeld-Adams 2013, Wu 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating "decreased incorporation of label from [14C]propionate and 5-[14C]methyltetrahydrofolate into cellular macromolecules (measuring function of methylmalonylCoA mutase and methionine synthase, respectively) and decreased synthesis of both AdoCbl and MeCbl from exogenous [57Co]-labeled CNCbl. In all cases, diagnosis was confirmed by complementation analysis (Lerner-Ellis 2006)." Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 20, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_This variant was identified as compound heterozygous withNM_015506.3:c.271dup. Criteria applied: PM3_VSTR, PM4_SUP, PP4 -

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.658_660del, results in the deletion of 1 amino acid(s) of the MMACHC protein (p.Lys220del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759243577, gnomAD 0.03%). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20631720, 21055272, 26149271, 26563984, 28218226). 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: 95707). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 13, 2021

Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2020

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MMACHC c.658_660delAAG (p.Lys220del) is an inframe deletion variant. Across a selection of the available literature, the p.Lys220del variant has been identified in a compound heterozygous state at least 25 individuals with cblC type of methylmalonic aciduria and homocystinuria(Lerner-Ellis et al. 2009; Liu et al. 2010; Weisfeld-Adams et al. 2013; Han et al. 2016; Wu et al. 2017). This variant is reported in 13.9% of disease alleles in the Chinese population (Liu et al. 2010). In one family, two affected siblings presented with late-onset disease and an initial presentation of manic-depressive psychosis (Wu et al. 2017). The p.Lys220del variant was absent from 50 control subjects (Lerner-Ellis et al. 2009) but is reported at a frequency of 0.000307 in the East Asian population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the p.Lys220del variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM4+PM3_VeryStrong+PP4+PP1 -

Nov 03, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 23, 2020

Neurology Department, Peking University First Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:3

Nov 17, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.658_660delAAG pathogenic variant in theMMACHC gene has also been reported previously in association with cblC deficiency and is reportedas a founder mutation in Chinese patients (Liu et al. 2010). The deletion causes the loss of a Lysinecodon at position 220, denoted p.Lys220del. -

Feb 09, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM3, PM4, PS4 -

May 29, 2013

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MMACHC-related disorder

Pathogenic:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MMACHC c.658_660delAAG variant is predicted to result in an in-frame deletion (p.Lys220del). This variant has been reported in both the homozygous and compound heterozygous states in individuals with combined methylmalonic aciduria and homocystinura, cblC type (for example, see Lerner-Ellis et al. 2006. PubMed ID: 16311595; Lerner-Ellis et al. 2009. PubMed ID: 19370762; Liu et al. 2010. PubMed ID: 20631720; Hu et al. 2018. PubMed ID: 30157807). This variant has been reported to be one of the most common causative MMACHC variants in Chinese patients (Liu et al. 2010. PubMed ID: 20631720; Hu et al. 2018. PubMed ID: 30157807). This variant is reported in 0.031% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Methylmalonic acidemia with homocystinuria cblC

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.8

Mutation Taster

=60/40

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over