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NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln) AND Cutis laxa

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 30, 2021
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:
RCV000779237.5

Allele description [Variation Report for NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln)]

NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln)

Gene:
PYCR1:pyrroline-5-carboxylate reductase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q25.3
Genomic location:
Preferred name:
NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln)
HGVS:
  • NC_000017.11:g.81934326C>T
  • NG_023032.1:g.7767G>A
  • NM_001282279.2:c.704G>A
  • NM_001282280.2:c.797G>A
  • NM_001282281.2:c.878G>A
  • NM_001330523.2:c.633+327G>A
  • NM_006907.4:c.797G>AMANE SELECT
  • NM_153824.3:c.797G>A
  • NP_001269208.1:p.Arg235Gln
  • NP_001269209.1:p.Arg266Gln
  • NP_001269210.1:p.Arg293Gln
  • NP_008838.2:p.Arg266Gln
  • NP_722546.1:p.Arg266Gln
  • NC_000017.10:g.79892202C>T
  • NM_006907.2:c.797G>A
  • NM_006907.3:c.797G>A
  • P32322:p.Arg266Gln
Protein change:
R235Q; ARG266GLN
Links:
UniProtKB: P32322#VAR_059076; OMIM: 179035.0001; OMIM: 179035.0004; dbSNP: rs121918374
NCBI 1000 Genomes Browser:
rs121918374
Molecular consequence:
  • NM_001330523.2:c.633+327G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001282279.2:c.704G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282280.2:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282281.2:c.878G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006907.4:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153824.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cutis laxa
Identifiers:
MONDO: MONDO:0016175; MedGen: C0010495; Human Phenotype Ontology: HP:0000973

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000915791Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)		Pathogenic
(Dec 19, 2018) 		germlineclinical testing

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

Citation Link,

SCV001821434Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Aug 30, 2021) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.

Dimopoulou A, Fischer B, Gardeitchik T, Schröter P, Kayserili H, Schlack C, Li Y, Brum JM, Barisic I, Castori M, Spaich C, Fletcher E, Mahayri Z, Bhat M, Girisha KM, Lachlan K, Johnson D, Phadke S, Gupta N, Simandlova M, Kabra M, David A, et al.

Mol Genet Metab. 2013 Nov;110(3):352-61. doi: 10.1016/j.ymgme.2013.08.009. Epub 2013 Aug 24.

PubMed [citation]
PMID:
24035636

Mutations in PYCR1 cause cutis laxa with progeroid features.

Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, et al.

Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413. Epub 2009 Aug 2. Erratum in: Nat Genet. 2022 Feb;54(2):213. doi: 10.1038/s41588-022-01013-2.

PubMed [citation]
PMID:
19648921
See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915791.1

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

Description

Across four different studies, the PYCR1 c.797G>A (p.Arg266Gln) variant was observed in a total of 11 individuals with cutis laxa, including eight homozygotes, two compound heterozygotes, and one proband of unknown zygosity (Reversade et al. 2009, Guernsey et al. 2009, Dimopoulou et al. 2013; Rahmati et al 2015). Family studies confirmed segregation of the p.Arg266Gln variant in a homozygous state with the disease phenotype. Guernsey et al. (2009) also determined the p.Arg266Gln missense variant results in an aberrant splice product which skips exon 6, deleting a conserved functional domain of the protein and generating a frameshift in the downstream exons leading to premature termination. The variant occurs at a highly conserved residue. The highest reported allele frequency was 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Arg266Gln variant is classified as pathogenic for autosomal recessive cutis laxa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821434.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: PYCR1 c.797G>A (p.Arg266Gln) results in a conservative amino acid change located in the Pyrroline-5-carboxylate reductase, dimerisation domain (IPR029036) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant is located in the exonic splice region that alters the last nucleotide of exon 6 adjacent to the canonical splice donor site. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping of exon 6 (Guernsey_2009). The variant allele was found at a frequency of 7.7e-05 in 247824 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PYCR1 causing Cutis Laxa - PYCR1 Related (7.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.797G>A has been reported in the literature in multiple individuals affected with autosomal recessive PYCR1 Related Cutis Laxa (example, Guernsey_2009, Dimopoulou_2013, Reversade_2009, Rahmati_2015, Kariminejad_2017). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jun 23, 2024