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NM_002693.3(POLG):c.3311C>T (p.Ser1104Phe) AND Progressive sclerosing poliodystrophy

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 15, 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:
RCV002622485.5

Allele description [Variation Report for NM_002693.3(POLG):c.3311C>T (p.Ser1104Phe)]

NM_002693.3(POLG):c.3311C>T (p.Ser1104Phe)

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.3(POLG):c.3311C>T (p.Ser1104Phe)
HGVS:
  • NC_000015.10:g.89318712G>A
  • NG_008218.2:g.21084C>T
  • NG_011736.1:g.79750G>A
  • NM_001126131.2:c.3311C>T
  • NM_002693.3:c.3311C>TMANE SELECT
  • NP_001119603.1:p.Ser1104Phe
  • NP_002684.1:p.Ser1104Phe
  • NP_002684.1:p.Ser1104Phe
  • LRG_765t1:c.3311C>T
  • LRG_500:g.79750G>A
  • LRG_765:g.21084C>T
  • LRG_765p1:p.Ser1104Phe
  • NC_000015.9:g.89861943G>A
  • NM_002693.2:c.3311C>T
Protein change:
S1104F
Molecular consequence:
  • NM_001126131.2:c.3311C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.3311C>T - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002969526Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Nov 15, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts.

Sitarz KS, Elliott HR, Karaman BS, Relton C, Chinnery PF, Horvath R.

Mol Genet Metab. 2014 May;112(1):57-63. doi: 10.1016/j.ymgme.2014.03.006. Epub 2014 Mar 28.

PubMed [citation]
PMID:
24725338
PMCID:
PMC4013927

Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO).

Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, Schaefer AM, Turnbull DM, Tiranti V, Zeviani M.

Neurology. 2003 Apr 22;60(8):1354-6.

PubMed [citation]
PMID:
12707443
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002969526.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1104 of the POLG protein (p.Ser1104Phe). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 24725338). ClinVar contains an entry for this variant (Variation ID: 1932285). 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 POLG protein function with a positive predictive value of 95%. This variant disrupts the p.Ser1104 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 12707443, 31521625), which suggests that this may be a clinically significant amino acid residue. 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.

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

Last Updated: Sep 29, 2024