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NM_033109.5(PNPT1):c.1592C>G (p.Thr531Arg) AND Combined oxidative phosphorylation defect type 13

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Feb 23, 2015
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_033109.5(PNPT1):c.1592C>G (p.Thr531Arg)]

NM_033109.5(PNPT1):c.1592C>G (p.Thr531Arg)

PNPT1:polyribonucleotide nucleotidyltransferase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_033109.5(PNPT1):c.1592C>G (p.Thr531Arg)
  • NC_000002.12:g.55647357G>C
  • NG_033012.1:g.51554C>G
  • NM_033109.3:c.1592C>G
  • NM_033109.5:c.1592C>GMANE SELECT
  • NP_149100.2:p.Thr531Arg
  • NC_000002.11:g.55874492G>C
  • NM_033109.4:c.1592C>G
  • NM_033109.5:c.1592C>G
Protein change:
dbSNP: rs374698153
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_033109.5:c.1592C>G - missense variant - [Sequence Ontology: SO:0001583]


Combined oxidative phosphorylation defect type 13
Combined oxidative phosphorylation deficiency 13
MONDO: MONDO:0013977; MedGen: C4706283; Orphanet: 319514; OMIM: 614932

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000245526Baylor Genetics - Adult_WES
criteria provided, single submitter

(Yang et al. 2013)
Likely pathogenic
(Feb 23, 2015)
maternalclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000786693Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG)
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenicgermlineresearch

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedmaternalyes33not providednot providedyesclinical testing
Unspecifiedgermlineyes11not providednot providednot providedresearch



Clinical whole-exome sequencing for the diagnosis of mendelian disorders.

Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, et al.

N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2.

PubMed [citation]

Molecular diagnostic experience of whole-exome sequencing in adult patients.

Posey JE, Rosenfeld JA, James RA, Bainbridge M, Niu Z, Wang X, Dhar S, Wiszniewski W, Akdemir ZH, Gambin T, Xia F, Person RE, Walkiewicz M, Shaw CA, Sutton VR, Beaudet AL, Muzny D, Eng CM, Yang Y, Gibbs RA, Lupski JR, Boerwinkle E, et al.

Genet Med. 2016 Jul;18(7):678-85. doi: 10.1038/gim.2015.142. Epub 2015 Dec 3.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Baylor Genetics - Adult_WES, SCV000245526.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providedyesclinical testing
PubMed (2)


Likely pathogenicity based on finding it three times in our laboratory in trans with another variant in affacted individuals: a 4-year-old male[with A507S] with global delays, speech articulation disorder, hypotonia; a 6-year-old male [with A507S] with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous); an 18-year-old male [with V509I] with profound intellectual disability, severe bilateral hearing loss, hypotonia, dysmorphisms, short stature, microcephaly, hyperextensibility, myopia, cataract, congenital heart disease, fused kidneys, small testicles, type II diabetes, immunodeficiency (healthy sib NOT compound heterozygous)

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyesnot providednot providednot provided
3not provided3not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG), SCV000786693.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Unspecified1not providednot providedresearch PubMed (3)


The heterozygous p.Thr531Arg variant in PNPT1 has been identified in the compound heterozygous state by our project in one individual with Combined Oxidative Phosphorylation Deficiency (COPD). The p.Thr531Arg variant has not been reported in the literature, but it has been reported in ClinVar (Variant ID: 209184). Baylor Laboratory reported this variant in 3 probands, however only 1/3 fit the current known clinical spectrum for PNPT1. Functional evidence (PNPase Western Blot, spectrophotometric enzyme assays, Dipstick assays, OXPHOS western blot) supports a pathogenic role for this variant and is consistent with other pathogenic variants (7 publications to date). The spectrophotometric enzyme assays conducted on fibroblasts were normal, which has been observed in other PNPT1- related cases including the one published in EJHG (Alodaib, A., et al. 2016) and others (Vedrenne, V., et al. 2012, Sato, R., et al. 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not provided1not provided

Last Updated: Jul 15, 2024