ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.1155A>C (p.Arg385Ser) (rs119103213)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153465 SCV000225392 pathogenic not provided 2013-11-26 criteria provided, single submitter clinical testing
GeneDx RCV000153465 SCV000616769 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The R385S variant has previously been reported in association with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency in several unrelated individuals who were homozygous for R385S, compound heterozygous for R385S and a second variant in MCCC1, or heterozygous for R385S with no second variant identified (Gallardo et al., 2001; Grunert et al., 2012; Shepard et al., 2014, Baumgartner et al., 2004). Functional analysis of R385S found that it is associated with significantly reduced enzyme activity compared to wild-type, and that R385S may have a dominant negative effect (Sloane et al., 2004; Baumgartner et al., 2004). The R385S variant is a semi-conservative amino acid substitution, that may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret R385S to be a pathogenic variant.
Invitae RCV000002007 SCV000656947 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 385 of the MCCC1 protein (p.Arg385Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs119103213, ExAC 0.03%). This variant has been reported as heterozygous, as homozygous, or in combination with other MCCC1 variants in multiple individuals affected with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 16835865, 22642865, 25356967). ClinVar contains an entry for this variant (Variation ID: 1930). Experimental studies have shown that this missense change abrogates MCCC1 enzymatic activity (PMID: 14680978, 15359379, 15868465). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000002007 SCV000916012 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2018-12-18 criteria provided, single submitter clinical testing Across a selection of literature the MCCC1 c.1155A>C (p.Arg385Ser) missense variant has been reported in at least 14 individuals with 3-MCC deficiency that were both symptomatic and asymptomatic. The variant was found in a homozygous state in three subjects and in a compound heterozygous state in 11 subjects (Gallardo et al. 2001; Baumgartner et al. 2001; Baumgartner et al. 2004; Dantas et al. 2005; Stadler et al. 2006; Morscher et al. 2012; Grunert et al. 2012; Shepard et al. 2015). The p.Arg385Ser variant was found in one of 216 control individuals and is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Exome Aggregation Consortium. In cultured skin fibroblasts from patients carrying the p.Arg385Ser variant, MCC activity was typically less than 10% of normal (Gallardo et al. 2001; Baumgartner et al. 2001; Stadler et al. 2006). Baumgartner et al. (2001) demonstrated that the p.Arg385Ser variant conferred no detectable MCC activity when expressed in a reference cell line, though normal amounts of the protein were detected, and Baumgartner et al. (2004) showed that the MCC activity was reduced when the p.Arg385Ser variant was co-transfected with the wild type allele, which indicated a dominant negative effect. Based on the evidence the p.Arg385Ser variant is classified as pathogenic for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000002007 SCV000022165 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2004-11-01 no assertion criteria provided literature only

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