rs863225029

chr17-15230965-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000304.4(PMP22):c.434del(p.Leu145ArgfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 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. L145L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PMP22 NM_000304.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.15

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-15230965-CA-C is Pathogenic according to our data. Variant chr17-15230965-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15230965-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMP22	NM_000304.4	c.434del	p.Leu145ArgfsTer10	frameshift_variant	5/5	ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9	c.434del	p.Leu145ArgfsTer10	frameshift_variant	5/5	1	NM_000304.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251328 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease, type IA Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 30, 2014	- -

Roussy-Lévy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2020

The c.434delT variant, located in coding exon 4 of the PMP22 gene, results from a deletion of one nucleotide at nucleotide position 434, causing a translational frameshift with a predicted alternate stop codon (p.L145Rfs*10). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of PMP22, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 16 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. This variant has been reported in several families with hereditary neuropathy with liability to pressure palsies (HNPP) (Taioli F et al. Brain, 2011 Feb;134:608-17; Benedetti S et al. Arch. Neurol., 2010 Dec;67:1498-505; Beydoun SR et al. J Clin Neuromuscul Dis, 2013 Sep;15:28-33; Manganelli F et al. J. Peripher. Nerv. Syst., 2014 Dec;19:292-8) and in families with other inherited neuropathy syndromes, including Charcot-Marie-Tooth disease (Vaeth S et al. Eur J Med Genet, 2019 Jan;62:1-8; Lerat J et al. Mol Genet Genomic Med, 2019 09;7:e839; Simpson BS et al. J Clin Neuromuscul Dis, 2010 Jun;11:187-90). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2023

Frameshift variant predicted to result in protein truncation, as the last 16 amino acids are replaced with 9 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23965407, 21149811, 32719652, 31393079, 29653220, 21252112) -

Charcot-Marie-Tooth disease, type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

This sequence change creates a premature translational stop signal (p.Leu145Argfs*10) in the PMP22 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the PMP22 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary neuropathy with liability to pressure palsy (HNPP) (PMID: 21149811, 21252112, 23965407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217238). 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)		0.0		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: rs863225029; hg19: chr17-15134282;