rs864622678

Variant names:

• chr17-15239509-CC-A
• rs864622678
• NM_000304.4:c.280_281delGGinsT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000304.4(PMP22):​c.280_281delGGinsT​(p.Gly94SerfsTer17) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G94S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.74
• Publications: 1 publications found

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]

PMP22 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 1E

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 35 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-15239509-CC-A is Pathogenic according to our data. Variant chr17-15239509-CC-A is described in ClinVar as [Pathogenic]. Clinvar id is 220861.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.280_281delGGinsT	p.Gly94SerfsTer17	frameshift_variant, missense_variant	Exon 4 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.280_281delGGinsT	p.Gly94SerfsTer17	frameshift_variant, missense_variant	Exon 4 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 21, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 2 nucleotides and inserts 1 nucleotide in exon 4 of the PMP22 mRNA (c.280_281delinsT), causing a frameshift at codon 94. This creates a premature translational stop signal in the last exon of the PMP22 mRNA (p.Gly94Serfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated PMP22 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. This variant has been observed to occur de novo in an affected individual tested at Invitae. In addition, a different variant (NM_000304.3:c.281delG) giving rise to a very similar protein effect  (p.Gly94Alafs*17) has been reported in several patients affected with CMT and Dejerine−Sottas syndrome (PMID: 9324088, 11545686, 11835375, 19067730, 26392352), which also suggests that the sequence change observed here is disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864622678; hg19: chr17-15142826;