NM_000533.5(PLP1):c.634T>C (p.Trp212Arg) AND Hereditary spastic paraplegia 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 24, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001920240.5

Allele description [Variation Report for NM_000533.5(PLP1):c.634T>C (p.Trp212Arg)]

NM_000533.5(PLP1):c.634T>C (p.Trp212Arg)

Genes:

RAB9B:RAB9B, member RAS oncogene family [Gene - OMIM - HGNC]
PLP1:proteolipid protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.2

Genomic location:

Preferred name:

NM_000533.5(PLP1):c.634T>C (p.Trp212Arg)

HGVS:

NC_000023.11:g.103788448T>C
NG_008863.2:g.16938T>C
NG_016452.2:g.48835A>G
NM_000533.5:c.634T>CMANE SELECT
NM_001128834.3:c.634T>C
NM_001305004.1:c.469T>C
NM_199478.3:c.529T>C
NP_000524.3:p.Trp212Arg
NP_001122306.1:p.Trp212Arg
NP_001291933.1:p.Trp157Arg
NP_955772.1:p.Trp177Arg
NC_000023.10:g.103043377T>C

Protein change:

W157R

Links:

dbSNP: rs2147766937

NCBI 1000 Genomes Browser:

rs2147766937

Molecular consequence:

NM_000533.5:c.634T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128834.3:c.634T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001305004.1:c.469T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_199478.3:c.529T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary spastic paraplegia 2 (SPG2)
Synonyms:: SPASTIC PARAPLEGIA 2, X-LINKED; Spastic paraplegia 2
Identifiers:: MONDO: MONDO:0010733; MedGen: C1839264; Orphanet: 99015; OMIM: 312920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002187498	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 24, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22695888, 11093273, 21679407, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002187498

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 24, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus-Merzbacher disease patient with a partial PLP1 duplication.

Shimojima K, Inoue T, Imai Y, Arai Y, Komoike Y, Sugawara M, Fujita T, Ideguchi H, Yasumoto S, Kanno H, Hirose S, Yamamoto T.

J Hum Genet. 2012 Sep;57(9):580-6. doi: 10.1038/jhg.2012.71. Epub 2012 Jun 14.

PubMed [citation]

PMID:: 22695888

Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease.

Cailloux F, Gauthier-Barichard F, Mimault C, Isabelle V, Courtois V, Giraud G, Dastugue B, Boespflug-Tanguy O.

Eur J Hum Genet. 2000 Nov;8(11):837-45.

PubMed [citation]

PMID:: 11093273

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002187498.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. This variant disrupts the p.Trp212 amino acid residue in PLP1. Other variant(s) that disrupt this residue have been observed in individuals with PLP1-related conditions (PMID: 22695888), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant is also known as W211R. This missense change has been observed in individuals with PLP1-related conditions (PMID: 11093273, 21679407; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 212 of the PLP1 protein (p.Trp212Arg).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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