NM_020376.4(PNPLA2):c.1337G>A (p.Gly446Asp) AND Neutral lipid storage myopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 26, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002642192.6

Allele description [Variation Report for NM_020376.4(PNPLA2):c.1337G>A (p.Gly446Asp)]

NM_020376.4(PNPLA2):c.1337G>A (p.Gly446Asp)

Gene:

PNPLA2:patatin like phospholipase domain containing 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_020376.4(PNPLA2):c.1337G>A (p.Gly446Asp)

HGVS:

NC_000011.10:g.824684G>A
NG_023394.1:g.10784G>A
NM_020376.3:c.1337G>A
NM_020376.4:c.1337G>AMANE SELECT
NP_065109.1:p.Gly446Asp
NC_000011.9:g.824684G>A

Protein change:

G446D

Molecular consequence:

NM_020376.4:c.1337G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neutral lipid storage myopathy (NLSDM)
Synonyms:: Neutral lipid storage disease with myopathy; Neutral lipid storage disease without ichthyosis
Identifiers:: MONDO: MONDO:0012545; MedGen: C1853136; Orphanet: 98908; OMIM: 610717

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002963956	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003813661	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 1, 2019)	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

SCV002963956

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 26, 2022)

germline

clinical testing

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

SCV003813661

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 1, 2019)

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

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002963956.2

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PNPLA2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 446 of the PNPLA2 protein (p.Gly446Asp).

#	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 Revvity Omics, Revvity, SCV003813661.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	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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