VCV001780171.3 - ClinVar

NM_000304.4(PMP22):c.178G>A (p.Glu60Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000304.4(PMP22):c.178G>A (p.Glu60Lys)

Variation ID: 1780171 Accession: VCV001780171.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p12 17: 15259094 (GRCh38) [ NCBI UCSC ] 17: 15162411 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 29, 2022	May 1, 2024	Mar 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000304.4:c.178G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000295.1:p.Glu60Lys	missense
NM_001281455.2:c.178G>A	NP_001268384.1:p.Glu60Lys	missense
NM_001281456.2:c.178G>A	NP_001268385.1:p.Glu60Lys	missense
NM_001330143.2:c.178G>A	NP_001317072.1:p.Glu60Lys	missense
NM_153321.3:c.178G>A	NP_696996.1:p.Glu60Lys	missense
NM_153322.3:c.178G>A	NP_696997.1:p.Glu60Lys	missense
NR_104017.2:n.273G>A		non-coding transcript variant
NC_000017.11:g.15259094C>T
NC_000017.10:g.15162411C>T
NG_007949.1:g.11234G>A
LRG_263:g.11234G>A
LRG_263t1:c.178G>A	LRG_263p1:p.Glu60Lys

... more HGVS ... less HGVS

Protein change

E60K

Other names

Canonical SPDI

NC_000017.11:15259093:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PMP22		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	407	525

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 24, 2020	RCV002404200.2
Charcot-Marie-Tooth disease, type I	Uncertain significance (1)	criteria provided, single submitter	Mar 30, 2023	RCV003581861.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease, type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004266791.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: ClinVar contains an entry for this variant (Variation ID: 1780171). In summary, the available evidence is currently insufficient to determine the role of this variant … (more) ClinVar contains an entry for this variant (Variation ID: 1780171). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PMP22-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 60 of the PMP22 protein (p.Glu60Lys). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. (less)
Uncertain significance (Jun 24, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002714440.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.178G>A variant (also known as p.E60K), located in coding exon 2 of the PMP22 gene, results from a G to A substitution at nucleotide … (more) The c.178G>A variant (also known as p.E60K), located in coding exon 2 of the PMP22 gene, results from a G to A substitution at nucleotide position 178. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glutamic acid at codon 60 to lysine, an amino acid with similar properties. Both the amino acid and nucleotide positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

ClinVar contains an entry for this variant (Variation ID: 1780171). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PMP22-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 60 of the PMP22 protein (p.Glu60Lys). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon.

Comment:

The c.178G>A variant (also known as p.E60K), located in coding exon 2 of the PMP22 gene, results from a G to A substitution at nucleotide position 178. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glutamic acid at codon 60 to lysine, an amino acid with similar properties. Both the amino acid and nucleotide positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000304.4(PMP22):c.178G>A (p.Glu60Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...