NM_015915.5(ATL1):c.1214T>G (p.Val405Gly) AND Hereditary spastic paraplegia 3A

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 3, 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:: RCV002862650.3

Allele description [Variation Report for NM_015915.5(ATL1):c.1214T>G (p.Val405Gly)]

NM_015915.5(ATL1):c.1214T>G (p.Val405Gly)

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.1214T>G (p.Val405Gly)

HGVS:

NC_000014.9:g.50628125T>G
NG_009028.1:g.100044T>G
NM_001127713.1:c.1214T>G
NM_015915.5:c.1214T>GMANE SELECT
NM_181598.4:c.1214T>G
NP_001121185.1:p.Val405Gly
NP_056999.2:p.Val405Gly
NP_056999.2:p.Val405Gly
NP_853629.2:p.Val405Gly
LRG_360t1:c.1214T>G
LRG_360t2:c.1214T>G
LRG_360:g.100044T>G
LRG_360p1:p.Val405Gly
LRG_360p2:p.Val405Gly
NC_000014.8:g.51094843T>G
NM_015915.4:c.1214T>G

Protein change:

V405G

Molecular consequence:

NM_001127713.1:c.1214T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015915.5:c.1214T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181598.4:c.1214T>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003227678	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 3, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31594988, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003227678

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 3, 2022)

germline

clinical testing

PubMed (2)
[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

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia.

Kadnikova VA, Rudenskaya GE, Stepanova AA, Sermyagina IG, Ryzhkova OP.

Sci Rep. 2019 Oct 8;9(1):14412. doi: 10.1038/s41598-019-50911-9.

PubMed [citation]

PMID:: 31594988
PMCID:: PMC6783457

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003227678.2

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

Description

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. This variant disrupts the p.Val405 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been observed in individuals with ATL1-related conditions (PMID: 31594988; Invitae), which suggests that this may be a clinically significant amino acid residue. 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 not expected to disrupt ATL1 protein function. This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 405 of the ATL1 protein (p.Val405Gly).

#	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: Sep 29, 2024

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