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

gnomAD frequency: 0.00008  dbSNP: rs119103213

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 385 of the MCCC1 protein (p.Arg385Ser). This variant is present in population databases (rs119103213, gnomAD 0.03%). This missense change has been observed in individuals with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 16835865, 22642865, 25356967). ClinVar contains an entry for this variant (Variation ID: 1930). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MCCC1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 14680978, 15359379, 15868465). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
Revvity Omics, Revvity	RCV000002007	SCV002017228	pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2021-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512665	SCV003689207	pathogenic	Inborn genetic diseases	2021-10-15	criteria provided, single submitter	clinical testing	The c.1155A>C (p.R385S) alteration is located in exon 11 (coding exon 11) of the MCCC1 gene. This alteration results from an A to C substitution at nucleotide position 1155, causing the arginine (R) at amino acid position 385 to be replaced by a serine (S). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (37/282844) total alleles studied. The highest observed frequency was 0.03% (35/129160) of European (non-Finnish) alleles. This alteration has been detected as compound heterozygous and homozygous in multiple unrelated individuals with MCC deficiency confirmed by biochemical analyses (Baumgartner, 2001; Gallardo, 2001; Baumgartner, 2004; Grünert, 2012; Smon, 2018). Multiple studies show that this alteration resulted in no detectable MCC activity and failed to restore MCC activity in MCCC1-deficient fibroblasts (Baumgartner, 2001; Desviat, 2003; Baumgartner, 2004). Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000153465	SCV003916862	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	MCCC1: PM3:Strong, PM1, PM2, PP1, PS3:Supporting
Baylor Genetics	RCV000002007	SCV004191951	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2023-10-10	criteria provided, single submitter	clinical testing
OMIM	RCV000002007	SCV000022165	pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2004-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001275509	SCV001460694	pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing