VCV001023623.7 - ClinVar

NM_000533.5(PLP1):c.232TTC[2] (p.Phe80del)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000533.5(PLP1):c.232TTC[2] (p.Phe80del)

Variation ID: 1023623 Accession: VCV001023623.7

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: Xq22.2 X: 103786505-103786507 (GRCh38) [ NCBI UCSC ] X: 103041434-103041436 (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	Mar 14, 2021	Jul 29, 2024	Mar 10, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000533.5:c.232TTC[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000524.3:p.Phe80del	inframe deletion
NM_000533.5:c.238_240delTTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001128834.3:c.232TTC[2]	NP_001122306.1:p.Phe80del	inframe deletion
NM_001305004.1:c.67TTC[2]	NP_001291933.1:p.Phe25del	inframe deletion
NM_199478.3:c.232TTC[2]	NP_955772.1:p.Phe80del	inframe deletion
NC_000023.11:g.103786505TTC[2]
NC_000023.10:g.103041434TTC[2]
NG_008863.2:g.14995TTC[2]
NG_016452.2:g.50770GAA[2]

... more HGVS ... less HGVS

Protein change

F25del, F80del

Other names

Canonical SPDI

NC_000023.11:103786504:TTCTTCTTC:TTCTTC

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

dbSNP: rs2074497991 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.
PLP1		Sufficient evidence for dosage pathogenicity	Sufficient evidence for dosage pathogenicity	GRCh38 GRCh37	17	613
RAB9B		-	-	GRCh38 GRCh37	3	598

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.
Hereditary spastic paraplegia 2	Uncertain significance (1)	criteria provided, single submitter	Apr 5, 2018	RCV001323702.8
Pelizaeus-Merzbacher disease	Likely pathogenic (1)	criteria provided, single submitter	Mar 10, 2021	RCV004595593.1

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 (Apr 05, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001514629.4 First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024	Comment: This variant, c.238_240delTTC, results in the deletion of 1 amino acid(s) of the PLP1 protein (p.Phe80del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.238_240delTTC, results in the deletion of 1 amino acid(s) of the PLP1 protein (p.Phe80del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with¬†Pelizaeus‚ÄìMerzbacher disease and has been reported¬†to be de novo in an individual affected with leukodystrophy and complex hereditary spastic paraplegia disease¬†(PMID:¬†23347225). This variant has also been referred to as p.Phe79del in the literature. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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. (less)
Likely pathogenic (Mar 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pelizaeus-Merzbacher disease (X-linked inheritance) Affected status: no, yes Allele origin: maternal, unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV005088436.1 First in ClinVar: Jul 29, 2024 Last updated: Jul 29, 2024	Publications: PubMed (1) PubMed: 19328639 Comment: This variant (c.238_240del, p.Phe80del) is an in-frame, single amino acid deletion that has not been observed in population databases (gnomAD). It has been found in … (more) This variant (c.238_240del, p.Phe80del) is an in-frame, single amino acid deletion that has not been observed in population databases (gnomAD). It has been found in 2 affected males within a family. It has been described in the literature (PMID 19328639) in a patient with nystagmus, hypomyelination on MRI, and abnormal auditory brain response findings. No functional studies have been published. (less) Observation 1: Clinical Features: Nystagmus (present) , Hypotonia (present) , Cerebellar ataxia (present) Age: 0-9 years Sex: male Tissue: blood Observation 2: Age: 10-19 years Sex: female Tissue: blood Observation 3: Sex: male Tissue: blood

Comment:

This variant, c.238_240delTTC, results in the deletion of 1 amino acid(s) of the PLP1 protein (p.Phe80del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with¬†Pelizaeus‚ÄìMerzbacher disease and has been reported¬†to be de novo in an individual affected with leukodystrophy and complex hereditary spastic paraplegia disease¬†(PMID:¬†23347225). This variant has also been referred to as p.Phe79del in the literature. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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.

Comment:

This variant (c.238_240del, p.Phe80del) is an in-frame, single amino acid deletion that has not been observed in population databases (gnomAD). It has been found in 2 affected males within a family. It has been described in the literature (PMID 19328639) in a patient with nystagmus, hypomyelination on MRI, and abnormal auditory brain response findings. No functional studies have been published.

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
Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications.	Shimojima K	Brain & development	2010	PMID: 19328639

Text-mined citations for rs2074497991 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000533.5(PLP1):c.232TTC[2] (p.Phe80del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2074497991 ...