Submissions for variant NM_052845.4(MMAB):c.197-1G>T

gnomAD frequency: 0.00001  dbSNP: rs763935916

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590462	SCV000699779	pathogenic	Methylmalonic acidemia	2016-07-08	criteria provided, single submitter	clinical testing	Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting this variant to disrupt a canonical acceptor sequence. These predictions were confirmed by functional assay (Dobson, 2002). The variant is present in the large, broad control population, ExAC with an allele frequency of 3/121374 (1/40458), which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene of 1/714 (0.0014). The variant was found in multiple affected individuals with an established diagnosis of methylmalonic aciduria. Fibroblast lines from homozygous carriers had decreased incorporation of label from [14C] propionate into cellular macromolecules and decreased synthesis of AdoCbl from exogenous [57Co]CNCb. Lastly, reputable databases/diagnostic centers classify the variant of interest as Pathogenic. Taken together, the variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000203326	SCV001149836	pathogenic	Methylmalonic aciduria, cblB type	2018-11-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203326	SCV001400676	pathogenic	Methylmalonic aciduria, cblB type	2024-03-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMAB are known to be pathogenic (PMID: 15781192, 16410054). This variant is present in population databases (rs763935916, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 16410054, 30022420). This variant is also known as IVS2-1G>T. ClinVar contains an entry for this variant (Variation ID: 219008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000203326	SCV002060277	pathogenic	Methylmalonic aciduria, cblB type	2021-11-15	criteria provided, single submitter	clinical testing	NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant classified as pathogenic in the context of methylmalonic acidemia, cblB type. c.197-1G>T has been observed in cases with relevant disease (PMID: 12471062, 24516753, 30022420, 26589311). Functional assessments of this variant are not available in the literature. c.197-1G>T has been observed in population frequency databases (gnomAD: SAS 0.03%). In summary, NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000203326	SCV004193146	pathogenic	Methylmalonic aciduria, cblB type	2024-02-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000590462	SCV004848703	pathogenic	Methylmalonic acidemia	2022-06-30	criteria provided, single submitter	clinical testing	The c.197-1G>T variant in MMAB (also known as IVS2-1G>T) has been reported, in the homozygous and compound heterozygous state, in several individuals affected with methylmalonic aciduria cobalamin B type (Lerner-Ellis 2006 PMID: 16410054, Dobson 2002 PMID: 12471062, Al-Shamsi 2014 PMID: 24516753, Shafaat 2018 PMID: 30022420, Al-Jasmi 2016 PMID: 26589311). It has also been reported in ClinVar (Variation ID 219008). It has also been identified in 1/67974 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MMAB gene is an established disease mechanism in autosomal recessive methylmalonic aciduria cobalamin B type. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic aciduria cobalamin B type. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_Strong.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798809	SCV005420359	pathogenic	Methylmalonic aciduria	2024-10-04	criteria provided, single submitter	research	PVS1, PS3,PM3 (modertae),PM2
Fulgent Genetics, Fulgent Genetics	RCV000203326	SCV005632654	pathogenic	Methylmalonic aciduria, cblB type	2024-05-31	criteria provided, single submitter	clinical testing
GeneReviews	RCV000203326	SCV000258532	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000203326	SCV000579473	pathogenic	Methylmalonic aciduria, cblB type		no assertion criteria provided	clinical testing	The observed variant is not reported in 1000 genomes database and is likely to be pathogenic by In Silico analysis using mutation taster.
Shieh Lab, University of California, San Francisco	RCV000203326	SCV001441636	pathogenic	Methylmalonic aciduria, cblB type	2020-10-19	no assertion criteria provided	research
Natera, Inc.	RCV000203326	SCV001459243	pathogenic	Methylmalonic aciduria, cblB type	2020-09-16	no assertion criteria provided	clinical testing
Baumgartner lab, University Children's Hospital Zurich	RCV000203326	SCV001738791	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing