NM_007055.4(POLR3A):c.[1909+22G>A;3337-11T>C] AND Neonatal pseudo-hydrocephalic progeroid syndrome

Clinical significance:Pathogenic (Last evaluated: Feb 13, 2019)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000755664.3

Alleles description [Variation Report for NM_007055.4(POLR3A):c.[1909+22G>A;3337-11T>C]]

NM_007055.4(POLR3A):c.1909+22G>A

Gene:
POLR3A:RNA polymerase III subunit A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q22.3
Genomic location:
Preferred name:
NM_007055.4(POLR3A):c.1909+22G>A
HGVS:
  • NC_000010.11:g.78009515C>T
  • NG_029648.1:g.25026G>A
  • NM_007055.4:c.1909+22G>AMANE SELECT
  • NC_000010.10:g.79769273C>T
  • NM_007055.3:c.1909+22G>A
Links:
OMIM: 614258.0010; dbSNP: rs191875469
NCBI 1000 Genomes Browser:
rs191875469
Molecular consequence:
  • NM_007055.4:c.1909+22G>A - intron variant - [Sequence Ontology: SO:0001627]

NM_007055.4(POLR3A):c.3337-11T>C

Gene:
POLR3A:RNA polymerase III subunit A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q22.3
Genomic location:
Preferred name:
NM_007055.4(POLR3A):c.3337-11T>C
HGVS:
  • NC_000010.11:g.77984023A>G
  • NG_029648.1:g.50518T>C
  • NM_007055.4:c.3337-11T>CMANE SELECT
  • NC_000010.10:g.79743781A>G
  • NM_007055.3:c.3337-11T>C
Links:
OMIM: 614258.0010; dbSNP: rs1564613755
NCBI 1000 Genomes Browser:
rs1564613755
Molecular consequence:
  • NM_007055.4:c.3337-11T>C - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Neonatal pseudo-hydrocephalic progeroid syndrome (WDRTS)
Synonyms:
Wiedemann-Rautenstrauch syndrome
Identifiers:
MONDO: MONDO:0009910; MedGen: C0406586; Orphanet: 3455; OMIM: 264090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000883063OMIMno assertion criteria providedPathogenic
(Feb 13, 2019)
germlineliterature only

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Progeria: a cell culture study and clinical report of familial incidence.

Rautenstrauch T, Snigula F.

Eur J Pediatr. 1977 Jan 26;124(2):101-11.

PubMed [citation]
PMID:
319005

A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2.

Akawi N, Ali B, Al Gazali L.

Birth Defects Res A Clin Mol Teratol. 2013 Jul;97(7):456-62. doi: 10.1002/bdra.23136. Epub 2013 May 20.

PubMed [citation]
PMID:
23696134
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000883063.32

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (6)

Description

In 6 patients from 4 unrelated families with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Paolacci et al. (2018) identified compound heterozygosity for 2 intronic variants, c.1909+22G-A (c.1909+22G-A, chr10.79769273, GRCh37) and c.3337-11T-C (c.3337-11T-C, chr10.79743781, GRCh37), on 1 allele of the POLR3A gene, and another mutation in POLR3A on the other allele. The patients comprised 1 (WRS002) of 2 sisters originally described by Rautenstrauch et al. (1977) (patient 'GM'), a 27-year-old Palestinian man and his 2 sibs (WRS004) who were reported by Akawi et al. (2013), a 21-year-old woman (WRS005) previously reported by Paolacci et al. (2017), and a German patient (WRS003). Analysis of RNA from patients WRS002 and WRS004 demonstrated that the c.1909+22G-A variant had a mild effect on exon 14 splicing, causing skipping of that exon and a frameshift resulting in a premature termination codon (Pro591MetfsTer9), whereas the c.3337-11T-C variant caused skipping of exon 26, resulting in an in-frame deletion (I1113_E1143del). In patient WRS002, the second mutation was another splice site mutation (c.1048+5G-T; 614258.0011) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24). The variant was present at very low frequency (0.0004%) in the gnomAD database. In the German patient (WRS003), the second mutation was a c.2474C-G transversion in the POLR3A gene, resulting in a ser825-to-ter (S825X; 614258.0012) substitution that was not found in the gnomAD database. In the 3 Palestinian sibs (WRS004), the second mutation was a c.1800C-T transition (614258.0013) within exon 14 of the POLR3A gene, a synonymous change that caused skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9); this variant was not found in the gnomAD database. cDNA analysis showed a strong additive effect on splicing by the c.1800C-T and c.1909+22G-A mutations together, with increased skipping of exon 14 compared to c.1909+22G-A alone. In patient WRS005, the second mutation was another splice site mutation (c.2617-1G-A; 614258.0004), present at very low frequency (0.002%) in the gnomAD database. Paolacci et al. (2018) noted that the Palestinian sibs' apparently unaffected father was homozygous for the mutant allele carrying the c.1909+22G-A and c.3337-11T-C variants, indicating that this allele does not cause a phenotype in homozygous state; the authors suggested that a specific mutation signature indicated by the combination of compound heterozygous mutations in POLR3A is necessary to cause WDRTS. In addition, the authors stated that the c.1909+22G-A mutation represents a relatively common variant, present at a minor allele frequency of 0.1% in the gnomAD database, and noted that it previously had been reported without the presence of the c.3337-11T-C variant on the same allele in patients with leukodystrophy.

In a 20-year-old woman (subject 2) with WDRTS who was originally studied by Garg et al. (2015) (patient NLD 1300.4), and an unrelated 21-year-old woman (subject 6) with WDRTS, Wambach et al. (2018) reported compound heterozygosity for the c.3337-11T-C mutation (c.3337-11T-C, NM_007055.3) and another mutation in POLR3A: in subject 6, the second mutation was a splice site mutation (c.2617-1G-A; 614258.0004), and in subject 2, it was a c.2005C-T transition, resulting in an arg669-to-ter (R669X; 614258.0017) substitution. Analysis of RNA from subject 2 demonstrated that the c.3337-11T-C mutation caused skipping of exon 26; however, in contrast to the findings of Paolacci et al. (2018), Wambach et al. (2018) found that the c.1909+22G-A variant (c.1909+22G-A, NM_007055.3) did not result in exon skipping.

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

Last Updated: Oct 8, 2021

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