Submissions for variant NM_032601.4(MCEE):c.178A>C (p.Lys60Gln)

gnomAD frequency: 0.00003  dbSNP: rs147401037

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186009	SCV000238971	uncertain significance	not specified	2017-03-08	criteria provided, single submitter	clinical testing	The K60Q variant in the MCEE gene has been reported previously as homozygous in a patient with methylmalonic aciduria (Gradinger et al., 2007). Gradinger et al. reported K60Q in a three year old patient with elevated methylmalonic acid excretion who presented with ataxia, deteriorated motor function, dysarthria, and mild spastic paraparesis. This variant is a non-conservative amino acid substitution of a positively charged Lysine with a neutral, polar Glutamine at a residue that is conserved in mammals. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. We interpret K60Q as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756325	SCV000884098	likely benign	not provided	2018-02-06	criteria provided, single submitter	clinical testing	The c.178A>C; p.Lys60Gln variant (rs147401037) was reported in the homozygous state in one patient with methylmalonic aciduria, ataxia, deteriorated motor function, dysarthria, and mild spastic paraparesis (Gradinger 2007). However, the patient’s protein activity level was normal, as measured by incorporation of propionate into cellular macromolecules (Gradinger 2007). This variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 1.5% (identified on 454 out of 30,778 chromosomes, including 10 homozygotes), and is found in the 1000 Genomes Project BEB (Bengali from Bangladesh) population with a frequency of 5.2% (9 out of 172 chromosomes). The lysine at position 60 is highly conserved, considering 13 species, and computational analyses of the effects of the p.Lys60Gln variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available evidence, the p.Lys60Gln variant is likely to be benign.
Invitae	RCV000203363	SCV001115025	likely benign	Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000203363	SCV001435154	likely benign	Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency		criteria provided, single submitter	research	The homozygous p.Lys60Gln variant in MCEE has been identified in an individual with methylmalonic aciduria (PMID: 17823972), but has also been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive methylmalonic aciduria.
CeGaT Center for Human Genetics Tuebingen	RCV000756325	SCV004154955	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	MCEE: BP4, BS1
GeneReviews	RCV000203363	SCV000258536	not provided	Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency		no assertion provided	literature only