NM_001166114.2(PNPLA6):c.1181A>G (p.Lys394Arg) AND Hereditary spastic paraplegia 39

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 17, 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:: RCV001960858.4

Allele description [Variation Report for NM_001166114.2(PNPLA6):c.1181A>G (p.Lys394Arg)]

NM_001166114.2(PNPLA6):c.1181A>G (p.Lys394Arg)

Gene:

PNPLA6:patatin like phospholipase domain containing 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_001166114.2(PNPLA6):c.1181A>G (p.Lys394Arg)

Other names:

p.Lys355Arg

HGVS:

NC_000019.10:g.7541996A>G
NG_013374.1:g.12845A>G
NM_001166111.2:c.1208A>G
NM_001166112.2:c.1064A>G
NM_001166113.1:c.1064A>G
NM_001166114.2:c.1181A>GMANE SELECT
NM_006702.4:c.1064A>G
NM_006702.5:c.1064A>G
NP_001159583.1:p.Lys403Arg
NP_001159584.1:p.Lys355Arg
NP_001159585.1:p.Lys355Arg
NP_001159586.1:p.Lys394Arg
NP_006693.3:p.Lys355Arg
NC_000019.9:g.7606882A>G
NM_006702.5:c.1064A>G

Protein change:

K355R

Links:

dbSNP: rs764509267

NCBI 1000 Genomes Browser:

rs764509267

Molecular consequence:

NM_001166111.2:c.1208A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001166112.2:c.1064A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001166113.1:c.1064A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001166114.2:c.1181A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006702.5:c.1064A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary spastic paraplegia 39 (SPG39)
Synonyms:: SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE; Spastic paraplegia 39; NTE related motor neuron disorder
Identifiers:: MONDO: MONDO:0012787; MedGen: C2677586; Orphanet: 139480; OMIM: 612020

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002243585	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 17, 2023)	germline	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

SCV002243585

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 17, 2023)

germline

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

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

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243585.3

#	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 lysine, which is basic and polar, with arginine, which is basic and polar, at codon 355 of the PNPLA6 protein (p.Lys355Arg). This variant is present in population databases (rs764509267, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PNPLA6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1463040). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PNPLA6 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Last Updated: Sep 29, 2024

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