rs200032855

Variant names:

• chr11-72358942-G-A
• rs200032855
• NM_030813.6:c.803C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:2
• Conservation: PhyloP100: 6.52
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria, type VIIB

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neutropenia, severe congenital, 9, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255672 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 187787.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria 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:1 Uncertain:1

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) -

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 -

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	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;.;.;.;.;.;.;.;.;.
PhyloP100		6.5
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200032855; hg19: chr11-72069986;