Submissions for variant NM_022132.4(MCCC2):c.1367_1368inv (p.Ala456Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521841	SCV000620039	pathogenic	not provided	2017-08-16	criteria provided, single submitter	clinical testing	The c.1367_1368delCAinsTG variant has been reported previously in a patient with 3-MCC deficiency who was homozgous for this variant and who was diagnosed after her infant was found to have elevated 3-hydroxyisovaleryl carnitine on newborn screening (Dantas et al. 2005). The c.1367_1368delCAinsTG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1367_1368delCAinsTG variant results in the normal Alanine codon at position 456 being replaced by a Valine, denoted p.Ala456Val (A456V). Expression studies found that A456V results in virtually no 3-MCC enzyme activity compared to wild-type (Grunert et al. 2012). Furthermore, in silico analysis predicts the A456V variant is probably damaging to the protein structure/function. In summary, we interpret this variant as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694490	SCV000822938	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 456 of the MCCC2 protein (p.Ala456Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with 3 methylcrotonyl-CoA carboxylase deficiency (Invitae). 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: 451352). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects MCCC2 function (PMID: 22642865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.