NM_144599.5(NIPA1):c.134C>G (p.Thr45Arg) AND Hereditary spastic paraplegia 6

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 13, 2023
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:: RCV000002628.11

Allele description [Variation Report for NM_144599.5(NIPA1):c.134C>G (p.Thr45Arg)]

NM_144599.5(NIPA1):c.134C>G (p.Thr45Arg)

Genes:

LOC130056709:ATAC-STARR-seq lymphoblastoid silent region 6259 [Gene]
NIPA1:NIPA magnesium transporter 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q11.2

Genomic location:

Preferred name:

NM_144599.5(NIPA1):c.134C>G (p.Thr45Arg)

HGVS:

NC_000015.10:g.22786790C>G
NG_009056.1:g.5566C>G
NM_001142275.1:c.-48+542C>G
NM_144599.5:c.134C>GMANE SELECT
NP_653200.2:p.Thr45Arg
NC_000015.9:g.23086278G>C
NM_144599.4:c.134C>G
Q7RTP0:p.Thr45Arg

Protein change:

T45R; THR45ARG

Links:

UniProtKB: Q7RTP0#VAR_023440; OMIM: 608145.0001; dbSNP: rs104894496

NCBI 1000 Genomes Browser:

rs104894496

Molecular consequence:

NM_001142275.1:c.-48+542C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_144599.5:c.134C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary spastic paraplegia 6 (SPG6)
Synonyms:: SPASTIC PARAPLEGIA 6, AUTOSOMAL DOMINANT; Spastic paraplegia 6; Familial spastic paraplegia autosomal dominant 3
Identifiers:: MONDO: MONDO:0010878; MedGen: C1838192; Orphanet: 100988; OMIM: 600363

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022786	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2003)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 7825577, 14508710
SCV001406668	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14508710, 17166836, 19091982, 20816793, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022786

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2003)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001406668

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 13, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q.

Fink JK, Wu CT, Jones SM, Sharp GB, Lange BM, Lesicki A, Reinglass T, Varvil T, Otterud B, Leppert M.

Am J Hum Genet. 1995 Jan;56(1):188-92.

PubMed [citation]

PMID:: 7825577
PMCID:: PMC1801321

NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6).

Rainier S, Chai JH, Tokarz D, Nicholls RD, Fink JK.

Am J Hum Genet. 2003 Oct;73(4):967-71. Epub 2003 Sep 23.

PubMed [citation]

PMID:: 14508710
PMCID:: PMC1180617

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000022786.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In the large family with many members affected with autosomal dominant hereditary spastic paraplegia (SPG6; 600363) reported by Fink et al. (1995), Rainier et al. (2003) demonstrated a 159C-G transversion in NIPA1 cDNA, resulting in a thr45-to-arg (T45R) substitution. The same mutation was found in an unrelated kindred with autosomal dominant hereditary spastic paraplegia that was too small for meaningful linkage analysis.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001406668.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the NIPA1 protein (p.Thr45Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 14508710). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2520). 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 disruptive. Experimental studies have shown that this missense change affects NIPA1 function (PMID: 17166836, 19091982, 20816793). For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 8, 2024

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