Submissions for variant NM_012213.3(MLYCD):c.475del (p.Ala159fs)

dbSNP: rs796051991

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186010	SCV000238972	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22104738, 12955715)
Illumina Laboratory Services, Illumina	RCV000778481	SCV000914741	uncertain significance	Deficiency of malonyl-CoA decarboxylase	2017-08-21	criteria provided, single submitter	clinical testing	The MLYCD c.475delG (p.Ala159ProfsTer20) variant has been reported in one study and is identified in a single homozygous individual with developmental delay, acidosis, and hypoglycemia (Wightman et al. 2003). Control data are unavailable for this variant, which is reported at a frequency of 0.000033 in the European (non-Finnish) population of the Genome Aggregation Database. Wightman et al. (2003) performed RT-PCR RNA analysis and found mRNA levels of the variant to be 12.8% of wild type and enzyme activity analysis was done using fibroblasts and found to be 14.9% of wild type. Based on the limited evidence and the potential impact of frameshift variants, the p.Ala159ProfsTer20 variant is classified as a variant of unknown significance but suspicious for pathogenicity for malonyl-CoA decarboxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000778481	SCV003443615	pathogenic	Deficiency of malonyl-CoA decarboxylase	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala159Profs*20) in the MLYCD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLYCD are known to be pathogenic (PMID: 12955715, 17186413). This variant is present in population databases (rs796051991, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with malonyl-CoA decarboxylase deficiency (PMID: 12955715). ClinVar contains an entry for this variant (Variation ID: 203813). For these reasons, this variant has been classified as Pathogenic.