chr3-183041679-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_020166.5(MCCC1):āc.1155A>Cā(p.Arg385Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_020166.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MCCC1 | NM_020166.5 | c.1155A>C | p.Arg385Ser | missense_variant | Exon 11 of 19 | ENST00000265594.9 | NP_064551.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251452Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135904
GnomAD4 exome AF: 0.000115 AC: 168AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 100AN XY: 727234
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74364
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:6
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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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. -
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not provided Pathogenic:4
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MCCC1: PM3:Strong, PM1, PM2, PM5:Supporting, PS3:Supporting -
Published functional studies found this variant is associated with significantly reduced MCC activity (PMID: 15359379, 14960587); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14960587, 31980526, 34426522, 31589614, 14680978, 27601257, 25356967, 22642865, 16010683, 11170888, 16773504, 15359379) -
Inborn genetic diseases Pathogenic:1
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. -
Methylcrotonyl-CoA carboxylase deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at