NM_144599.5(NIPA1):c.403G>A (p.Val135Met) AND Hereditary spastic paraplegia 6

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 27, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000640458.11

Allele description [Variation Report for NM_144599.5(NIPA1):c.403G>A (p.Val135Met)]

NM_144599.5(NIPA1):c.403G>A (p.Val135Met)

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.403G>A (p.Val135Met)

HGVS:

NC_000015.10:g.22820398G>A
NG_009056.1:g.39174G>A
NM_001142275.1:c.178G>A
NM_144599.5:c.403G>AMANE SELECT
NP_001135747.1:p.Val60Met
NP_653200.2:p.Val135Met
NC_000015.9:g.23052670C>T
NM_144599.4:c.403G>A

Protein change:

V135M

Links:

dbSNP: rs763295984

NCBI 1000 Genomes Browser:

rs763295984

Molecular consequence:

NM_001142275.1:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_144599.5:c.403G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000762049	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001451133	Paris Brain Institute, Inserm - ICM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000762049

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 27, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001451133

Paris Brain Institute, Inserm - ICM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV000762049.6

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 135 of the NIPA1 protein (p.Val135Met). This variant is present in population databases (rs763295984, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NIPA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533363). 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. 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.

#	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

From Paris Brain Institute, Inserm - ICM, SCV001451133.1

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

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

Last Updated: Feb 20, 2024

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