12-109561051-CCGG-CCGGCGG

Variant names:

• chr12-109561051-C-CCGG
• rs864309512
• NM_052845.4:c.570_572dupCCG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_052845.4(MMAB):​c.570_572dupCCG​(p.Arg191dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000000686 in 1,458,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R191R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MMAB NM_052845.4 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.67
• Publications: 1 publications found

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

MMAB Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblB type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_052845.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_052845.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-109561051-C-CCGG is Pathogenic according to our data. Variant chr12-109561051-C-CCGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 218327.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
MMAB	NM_052845.4	c.570_572dupCCG	p.Arg191dup	disruptive_inframe_insertion	Exon 7 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.570_572dupCCG	p.Arg191dup	disruptive_inframe_insertion	Exon 7 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458582 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 725848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Pathogenic:3

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects MMAB function (PMID: 24813872). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 218327). This variant has been observed in individual(s) with clinical features of methylmalonic aciduria cblB type (PMID: 24813872). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.570_572dup, results in the insertion of 1 amino acid(s) of the MMAB protein (p.Arg191dup), but otherwise preserves the integrity of the reading frame. -

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Methylmalonic acidemia Pathogenic:1

Dec 09, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MMAB c.570_572dupCCG (p.Arg191dup) results in an in-frame duplication in the Cobalamin adenosyltransferase-like domain (IPR016030), that is predicted to duplicate 1 amino acid into the encoded protein. The variant was absent in 248880 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.570_572dupCCG has been reported in the literature in a compound heterozygous individual identified through newborn screening, who is documented as clinically asymptomatic and follows a disease management plan to avoid metabolic crises. Through family genetic study, his sibling was identified with the same genotype, exhibiting a slight increase in urine methylmalonic acid, but clinically asymptomatic (Brasil_2015, 2018). This report does not provide unequivocal conclusions about association of the variant with Methylmalonic Acidemia. Nevertheless, Brasil et al (2015) carried out functional assessment of the variant and concluded it to be a severely destabilizing mutation with concomitant greatly reduced ATR activity, while p.His183Leu (the variant in trans in the two identified siblings) has a milder effect (which may explain their asymptomatic status). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. A different in-frame duplication involving 5 amino acids within this region of the protein (c.563_577dup, p.Val188_Ala192dup) is reported in multiple individuals affected with Methylmalonic Acidemia and is classified as pathogenic via internal testing. Additionally, missense variants affecting the 191 amino acid residue or neighboring residues (e.g. p.Arg191Gln, p.Arg191Trp, p.Arg190His, p.Arg190Gly, p.Arg190Cys), are cited in ClinVar and HGMD as pathogenic and disease-associated, suggesting this region is important for protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864309512; hg19: chr12-109998856;