Submissions for variant NM_015506.3(MMACHC):c.658_660del (p.Lys220del)

dbSNP: rs398124296

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081744	SCV000321903	pathogenic	not provided	2015-11-17	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	RCV000081744	SCV000331408	pathogenic	not provided	2013-05-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000272939	SCV000485816	pathogenic	Cobalamin C disease	2016-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000272939	SCV000919673	pathogenic	Cobalamin C disease	2018-10-15	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000272939	SCV000935584	pathogenic	Cobalamin C disease	2024-02-12	criteria provided, single submitter	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.
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	RCV000272939	SCV001622426	pathogenic	Cobalamin C disease	2021-05-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000272939	SCV001786619	pathogenic	Cobalamin C disease	2020-11-02	criteria provided, single submitter	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000272939	SCV002026396	pathogenic	Cobalamin C disease	2021-12-20	criteria provided, single submitter	clinical testing	_x000D_This variant was identified as compound heterozygous withNM_015506.3:c.271dup. Criteria applied: PM3_VSTR, PM4_SUP, PP4
Fulgent Genetics, Fulgent Genetics	RCV000272939	SCV002791009	pathogenic	Cobalamin C disease	2024-02-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000272939	SCV004178223	pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000272939	SCV004193166	pathogenic	Cobalamin C disease	2024-03-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000081744	SCV004226714	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	PM1, PM3, PM4, PS4
OMIM	RCV000272939	SCV000045077	pathogenic	Cobalamin C disease	2010-09-01	no assertion criteria provided	literature only
Neurology Department, Peking University First Hospital	RCV000272939	SCV001423140	pathogenic	Cobalamin C disease	2020-04-23	no assertion criteria provided	research
Natera, Inc.	RCV001275218	SCV001460142	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	RCV000272939	SCV003838959	pathogenic	Cobalamin C disease		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755765	SCV005362935	pathogenic	MMACHC-related disorder	2024-06-10	no assertion criteria provided	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.