NM_030813.6:c.803C>T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV000775147: Experimental studies have shown that this missense change affects CLPB function (PMID:32573439)." and additional evidence is available in ClinVar. 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000775147: Experimental studies have shown that this missense change affects CLPB function (PMID: 32573439).; SCV004780302: "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)."; SCV005421337: Published functional studies suggest this variant is associated with impaired protein disaggregation (PMID: 37041140)
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030813.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	NM_030813.6	MANE Plus Clinical	c.803C>T	p.Thr268Met	missense	Exon 6 of 17	NP_110440.1	A0A140VK11
	CLPB	NM_001258392.3	MANE Select	c.713C>T	p.Thr238Met	missense	Exon 5 of 16	NP_001245321.1	Q9H078-2
	CLPB	NM_001258394.3		c.668C>T	p.Thr223Met	missense	Exon 7 of 18	NP_001245323.1	Q9H078-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	ENST00000294053.9	TSL:1 MANE Plus Clinical	c.803C>T	p.Thr268Met	missense	Exon 6 of 17	ENSP00000294053.3	Q9H078-1
	CLPB	ENST00000538039.6	TSL:2 MANE Select	c.713C>T	p.Thr238Met	missense	Exon 5 of 16	ENSP00000441518.1	Q9H078-2
	CLPB	ENST00000955687.1		c.776C>T	p.Thr259Met	missense	Exon 5 of 16	ENSP00000625746.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	3-methylglutaconic aciduria, type VIIB (4)
1	1	-	not provided (2)
1	-	-	CLPB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		6.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.76		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;