rs863225083

chr6-42967410-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000287.4(PEX6):c.1841del(p.Leu614ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000236 in 1,613,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L614L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PEX6 NM_000287.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.35

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-42967410-CA-C is Pathogenic according to our data. Variant chr6-42967410-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42967410-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.1841del	p.Leu614ArgfsTer5	frameshift_variant	8/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.1841del	p.Leu614ArgfsTer5	frameshift_variant	8/17	1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.1841del	p.Leu614ArgfsTer5	frameshift_variant	8/15	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248744 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134882

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461114 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726800

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: 0.0000333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heimler syndrome 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 10, 2023	- -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 23, 2018

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.1841delT (p.L614Rfs*5) alteration, located in exon 8 (coding exon 8) of the PEX6 gene, consists of a deletion of one nucleotide at position 1841, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was reported in the compound heterozygous state with a missense alteration in two siblings with a diagnosis of Heimler syndrome and clinical features of amelogenesis imperfecta, bilateral profound sensorineural hearing loss, retinal pigmentation, abnormal nails, and normal intellect (Ratbi, 2015). In vitro transfection studies of this alteration in peroxisome-deficient cells resulted in no functional complementation (Ratbi, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2018

The c.1841delT variant in the PEX6 gene has been reported previously in twin siblings with Heimler syndrome who also harbored a PEX6 missense variant, although parental studies were not performed to determine the phase of these two variants (Ratbi et al., 2015). Functional studies using in vitro transfection of the c.1841delT variant showed minimal functional complementation of peroxisome biogenesis in peroxisome deficient cells. The c.1841delT variant causes a frameshift starting with codon Leucine 614, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Leu614ArgfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1841delT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1841delT as a pathogenic variant. -

Peroxisome biogenesis disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change creates a premature translational stop signal (p.Leu614Argfs*5) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Heimler syndrome (PMID: 26387595). ClinVar contains an entry for this variant (Variation ID: 217426). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs863225083; hg19: chr6-42935148;