rs786205137
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5
The NM_030813.6(CLPB):c.1233G>A(p.Met411Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,058 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_030813.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLPB | NM_030813.6 | c.1233G>A | p.Met411Ile | missense_variant | 11/17 | ENST00000294053.9 | |
CLPB | NM_001258392.3 | c.1143G>A | p.Met381Ile | missense_variant | 10/16 | ENST00000538039.6 | |
LOC124902708 | XR_007062766.1 | n.1910C>T | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLPB | ENST00000294053.9 | c.1233G>A | p.Met411Ile | missense_variant | 11/17 | 1 | NM_030813.6 | P4 | |
CLPB | ENST00000538039.6 | c.1143G>A | p.Met381Ile | missense_variant | 10/16 | 2 | NM_001258392.3 | A1 | |
ENST00000546065.1 | n.190C>T | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251286Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135788
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461866Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
3-methylglutaconic aciduria, type VIIB Pathogenic:1Uncertain:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 05, 2015 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2023 | 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. Experimental studies have shown that this missense change affects CLPB function (PMID: 25597510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 187783). This missense change has been observed in individual(s) with clinical features of mild 3-methylglutaconic aciduria (PMID: 25597510). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs786205137, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 411 of the CLPB protein (p.Met411Ile). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2023 | Identified in a family with cataracts and neutropenia who also carried a second variant in CLPB. Parental studies were not conducted to determine if these variants were on the same (in cis) or opposite (in trans) alleles (Wortmann et al., 2015); Published functional studies suggest a damaging effect on enzymatic activity (Wortmann et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27137937, 25597510, 28687938, 27891836) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 21, 2022 | The c.1233G>A (p.M411I) alteration is located in exon 11 (coding exon 11) of the CLPB gene. This alteration results from a G to A substitution at nucleotide position 1233, causing the methionine (M) at amino acid position 411 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251286) total alleles studied. The highest observed frequency was <0.01% (2/113598) of European (non-Finnish) alleles. This alteration has been reported in two affected siblings with elevated urinary excretion of 3-methylglutaconic acid, neutropenia, and cataracts (Wortmann, 2015). Another variant, p.Y617C, in CLPB was found in both patients; however, their parents were not tested to confirm if the variants were in cis or in trans. Functional studies using zebrafish showed that this alteration does not lead to changes in the integrity of the cerebellum in zebrafish embryos compared to wildtype; an in vitro assay showed that ATPase activity for this alteration was significantly decreased (Wortmann, 2015). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at