NM_002693.3(POLG):c.2218A>G (p.Asn740Asp) AND Progressive sclerosing poliodystrophy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 11, 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:: RCV001372628.12

Allele description [Variation Report for NM_002693.3(POLG):c.2218A>G (p.Asn740Asp)]

NM_002693.3(POLG):c.2218A>G (p.Asn740Asp)

Genes:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
POLGARF:POLG alternative reading frame [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.2218A>G (p.Asn740Asp)

Other names:

p.N740D:AAC>GAC

HGVS:

NC_000015.10:g.89323451T>C
NG_008218.2:g.16345A>G
NM_001126131.2:c.2218A>G
NM_002693.3:c.2218A>GMANE SELECT
NP_001119603.1:p.Asn740Asp
NP_002684.1:p.Asn740Asp
NP_002684.1:p.Asn740Asp
LRG_765t1:c.2218A>G
LRG_765:g.16345A>G
LRG_765p1:p.Asn740Asp
NC_000015.9:g.89866682T>C
NM_002693.2:c.2218A>G
NM_002693.3:c.2218A>G

Protein change:

N740D

Links:

dbSNP: rs78347903

NCBI 1000 Genomes Browser:

rs78347903

Molecular consequence:

NM_001126131.2:c.2218A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.2218A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:: Alpers disease; Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis; Alpers progressive infantile poliodystrophy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008758; MedGen: C0205710; Orphanet: 726; OMIM: 203700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001569304	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35307828, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001569304

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 11, 2023)

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

Genetic analysis reveals novel variants for vascular cognitive impairment.

Mönkäre S, Kuuluvainen L, Schleutker J, Bras J, Roine S, Pöyhönen M, Guerreiro R, Myllykangas L.

Acta Neurol Scand. 2022 Jul;146(1):42-50. doi: 10.1111/ane.13613. Epub 2022 Mar 20.

PubMed [citation]

PMID:: 35307828
PMCID:: PMC9314039

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

Details of each submission

From Invitae, SCV001569304.4

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

Description

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 740 of the POLG protein (p.Asn740Asp). This variant is present in population databases (rs78347903, gnomAD 0.005%). This missense change has been observed in individual(s) with vascular dementia (PMID: 35307828). ClinVar contains an entry for this variant (Variation ID: 206519). 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 POLG protein function with a negative predictive value of 95%. 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: Jun 2, 2024

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