rs398124296

Positions:

• chr1-45509021-CAGA-C
• chr1-45509021-CAGA-CAGAAGA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_015506.3(MMACHC):​c.658_660del​(p.Lys220del) variant causes a 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 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 8.76

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 13 ACMG points.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 50 pathogenic changes around while only 14 benign (78%) in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 95707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45509021-CAGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.658_660del	p.Lys220del	inframe_deletion	4/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.487_489del	p.Lys163del	inframe_deletion	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.658_660del	p.Lys220del	inframe_deletion	4/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.487_489del	p.Lys163del	inframe_deletion	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152198 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249382 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135292

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461864 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 727234

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74494

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000140

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Pathogenic:12

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 20, 2021	_x000D_This variant was identified as compound heterozygous withNM_015506.3:c.271dup. Criteria applied: PM3_VSTR, PM4_SUP, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	research	Neurology Department, Peking University First Hospital	Apr 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 02, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	May 13, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	PM1, PM3, PM4, PS4 -

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: rs398124296; hg19: chr1-45974693;