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NM_015915.5(ATL1):c.1484G>A (p.Arg495Gln) AND Hereditary spastic paraplegia 3A

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 9, 2022
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:
RCV002599329.3

Allele description [Variation Report for NM_015915.5(ATL1):c.1484G>A (p.Arg495Gln)]

NM_015915.5(ATL1):c.1484G>A (p.Arg495Gln)

Gene:
ATL1:atlastin GTPase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q22.1
Genomic location:
Preferred name:
NM_015915.5(ATL1):c.1484G>A (p.Arg495Gln)
HGVS:
  • NC_000014.9:g.50628395G>A
  • NG_009028.1:g.100314G>A
  • NM_001127713.1:c.1484G>A
  • NM_015915.5:c.1484G>AMANE SELECT
  • NM_181598.4:c.1484G>A
  • NP_001121185.1:p.Arg495Gln
  • NP_056999.2:p.Arg495Gln
  • NP_056999.2:p.Arg495Gln
  • NP_853629.2:p.Arg495Gln
  • LRG_360t1:c.1484G>A
  • LRG_360t2:c.1484G>A
  • LRG_360:g.100314G>A
  • LRG_360p1:p.Arg495Gln
  • LRG_360p2:p.Arg495Gln
  • NC_000014.8:g.51095113G>A
  • NM_015915.4:c.1484G>A
Protein change:
R495Q
Molecular consequence:
  • NM_001127713.1:c.1484G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015915.5:c.1484G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181598.4:c.1484G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary spastic paraplegia 3A (SPG3A)
Synonyms:
SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; FAMILIAL SPASTIC PARAPLEGIA, AUTOSOMAL DOMINANT, 1; SPG3; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008437; MedGen: C2931355; Orphanet: 100984; OMIM: 182600

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003496733Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(May 9, 2022) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.

Dürr A, Camuzat A, Colin E, Tallaksen C, Hannequin D, Coutinho P, Fontaine B, Rossi A, Gil R, Rousselle C, Ruberg M, Stevanin G, Brice A.

Arch Neurol. 2004 Dec;61(12):1867-72.

PubMed [citation]
PMID:
15596607

The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy.

Scarano V, Mancini P, Criscuolo C, De Michele G, Rinaldi C, Tucci T, Tessa A, Santorelli FM, Perretti A, Santoro L, Filla A.

J Neurol. 2005 Aug;252(8):901-3. Epub 2005 Mar 8.

PubMed [citation]
PMID:
15742100
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003496733.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 495 of the ATL1 protein (p.Arg495Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATL1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL1 protein function. This variant disrupts the p.Arg495 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15596607, 15742100, 17502470, 20718791, 20932283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024