rs200032855

chr11-72358942-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_030813.6(CLPB):c.803C>T(p.Thr268Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,776 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 6.52

Genes affected

CLPB (HGNC:30664): (ClpB family mitochondrial disaggregase) This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 11-72358942-G-A is Pathogenic according to our data. Variant chr11-72358942-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72358942-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6	c.803C>T	p.Thr268Met	missense_variant	6/17	ENST00000294053.9
CLPB	NM_001258392.3	c.713C>T	p.Thr238Met	missense_variant	5/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.803C>T	p.Thr268Met	missense_variant	6/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.713C>T	p.Thr238Met	missense_variant	5/16	2	NM_001258392.3	A1
	ENST00000537727.1	n.377+3594G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251356 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461776 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Pathogenic:2 Other:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 268 of the CLPB protein (p.Thr268Met). This variant is present in population databases (rs200032855, gnomAD 0.002%). This missense change has been observed in individuals with 3-methylglutaconic aciduria (PMID: 25597511, 28687938). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 187787). 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. Experimental studies have shown that this missense change affects CLPB function (PMID: 32573439). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely pathogenic and reported on 03-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not provided, no classification provided	literature only	GeneReviews	-	- -

CLPB-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2023

The CLPB c.803C>T variant is predicted to result in the amino acid substitution p.Thr268Met. This variant has been reported in the homozygous state in individuals from multiple families with 3-methylglutaconic aciduria (Saunders et al. 2015. PubMed ID: 25597511; Pronicka et al. 2017. PubMed ID: 28687938). Immunoblot analysis of patient fibroblasts showed no detectable CLPB protein (Saunders et al. 2015. PubMed ID: 25597511). In vitro functional studies have also demonstrated that this variant affects CLPB function (Cupo et al. 2020. PubMed ID: 32573439; Lee et al. 2023. PubMed ID: 37041140). This variant is reported in 0.0015% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-72069986-G-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;.;.;D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.;D;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.
Vest4		0.69
MutPred		0.76		Gain of methylation at K265 (P = 0.1645);.;.;.;.;Gain of methylation at K265 (P = 0.1645);.;.;.;Gain of methylation at K265 (P = 0.1645);
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.76
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200032855; hg19: chr11-72069986;