NM_030813.6:c.803C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T268T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CLPB
NM_030813.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:2

Conservation

PhyloP100: 6.52

Variant links:

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]

CLPB links:

ENSG00000255672 (HGNC:):

ENSG00000255672 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187787.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, not_provided=2, Uncertain_significance=1}. Variant chr11-72358942-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6 link	c.803C>T	p.Thr268Met	missense_variant	Exon 6 of 17	ENST00000294053.9	NP_110440.1	Q9H078-1A0A140VK11
CLPB	NM_001258392.3 link	c.713C>T	p.Thr238Met	missense_variant	Exon 5 of 16	ENST00000538039.6	NP_001245321.1	Q9H078-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9 link	c.803C>T	p.Thr268Met	missense_variant	Exon 6 of 17	1	NM_030813.6	ENSP00000294053.3		Q9H078-1
CLPB	ENST00000538039.6 link	c.713C>T	p.Thr238Met	missense_variant	Exon 5 of 16	2	NM_001258392.3	ENSP00000441518.1		Q9H078-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251356

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135856

show subpopulations

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:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727194

show subpopulations

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.:

Alfa

AF:

0.0000712

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB

Pathogenic:2Other:2

Feb 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 autosomal recessive 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

Pathogenic:1Uncertain:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLPB: PM2, PM3, PS3:Supporting -

Jun 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest this variant is associated with impaired protein disaggregation (PMID: 37041140); 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: 27137937, 28687938, 27891836, 32573439, 37163603, 36745679, 25597511, 37041140) -

CLPB-related disorder

Pathogenic:1

Nov 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

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

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.70

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over