rs61752132

Positions:

• chr22-18078510-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001127649.3(PEX26):​c.134T>C​(p.Leu45Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000775 in 1,419,736 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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 4.09

Genes affected

PEX26 (HGNC:22965): (peroxisomal biogenesis factor 26) This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 22-18078510-T-C is Pathogenic according to our data. Variant chr22-18078510-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2157.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.134T>C	p.Leu45Pro	missense_variant	1/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.134T>C	p.Leu45Pro	missense_variant	2/6		NP_060399.1
PEX26	NM_001199319.2	c.134T>C	p.Leu45Pro	missense_variant	2/5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.134T>C	p.Leu45Pro	missense_variant	1/5	1	NM_001127649.3	ENSP00000382648	P1
	ENST00000607927.1	n.375A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000775 AC: 11 AN: 1419736 Hom.: 0 Cov.: 31 AF XY: 0.00000711 AC XY: 5 AN XY: 703364

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The PEX26 c.134T>C (p.Leu45Pro) missense variant was reported in a compound heterozygous state with a second missense variant in one individual with infantile Refsum disease, which is part of the Zellweger spectrum (Matsumoto et al. 2003). Control data are not available and allele frequency information for this variant is not reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Expression of the p.Leu45Pro variant in a PEX26-deficient CHO cell line showed that the variant did not restore impaired peroxisome biogenesis (Matsumoto et al. 2003, Weller et al. 2005) and interfered with interactions with other PEX proteins (Furuki et al. 2006; Tamura et al. 2014). Based on the evidence, the p.Leu45Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for Zellweger syndrome spectrum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Peroxisome biogenesis disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 18, 2024

Variant summary: PEX26 c.134T>C (p.Leu45Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-06 in 1571928 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PEX26 causing Zellweger Syndrome (7e-06 vs 0.0016), allowing no conclusion about variant significance. c.134T>C has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with infantile Refsum disease (example, Matsumoto_2003, Weller_2005). Multiple functional studies using in vitro cell lines or a PEX26-null patient fibroblast background found that this variant reduced import activity, reduced binding to partner proteins, and cannot complement PEX26-null cells; however, protein levels and localization are not significantly different from wild type controls (example, Furuki_2006, Matsumoto_2003, Tamura_2014, Weller_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16257970, 12851857, 25016021, 15858711). ClinVar contains an entry for this variant (Variation ID: 2157). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Peroxisome biogenesis disorder 7B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2003

- -

Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2022

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 45 of the PEX26 protein (p.Leu45Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile Refsum disease (PMID: 12851857). ClinVar contains an entry for this variant (Variation ID: 2157). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PEX26 function (PMID: 12851857, 16257970, 25016021). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D;D;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T;.;T;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	0.098	A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	.;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.97
MutPred		0.90		Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);
MVP		0.99
MPC		0.88
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.85

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: rs61752132; hg19: chr22-18561276;