rs202197951
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_020166.5(MCCC1):c.388G>A(p.Gly130Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,754 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G130V) has been classified as Uncertain significance.
Frequency
Consequence
NM_020166.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC1 | NM_020166.5 | c.388G>A | p.Gly130Ser | missense_variant | 5/19 | ENST00000265594.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC1 | ENST00000265594.9 | c.388G>A | p.Gly130Ser | missense_variant | 5/19 | 1 | NM_020166.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251026Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135802
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461574Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727102
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74400
ClinVar
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 1 deficiency Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2023 | This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 27601257, 31730530). This variant is present in population databases (rs202197951, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the MCCC1 protein (p.Gly130Ser). ClinVar contains an entry for this variant (Variation ID: 344315). 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. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: MCCC1 c.388G>A (p.Gly130Ser) results in a non-conservative amino acid change located in the Biotin carboxylase-like, N-terminal domain (IPR005481) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251026 control chromosomes. c.388G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Fonseca_2016, Wang_2019, Wang_2019, Yang_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27601257, 31737040, 31730530, 30838026). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
MCCC1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 19, 2023 | The MCCC1 c.388G>A variant is predicted to result in the amino acid substitution p.Gly130Ser. This variant has been reported in the homozygous state or heterozygous state with a second MCCC1 variant in two asymptomatic individuals with 3-methylcrotonyl-CoA carboxylase deficiency, identified by newborn screening (Fonseca et al. 2016. PubMed ID: 27601257; Wang et al. 2019. PubMed ID: 31730530). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-182790257-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at