NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000489299.9

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Nucleotide
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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000577023	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 2, 2022)	germline	clinical testing	Citation Link,
SCV001581116	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19576563, 19648921, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000577023

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 2, 2022)

germline

clinical testing

Citation Link,

SCV001581116

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.

Guernsey DL, Jiang H, Evans SC, Ferguson M, Matsuoka M, Nightingale M, Rideout AL, Provost S, Bedard K, Orr A, Dubé MP, Ludman M, Samuels ME.

Am J Hum Genet. 2009 Jul;85(1):120-9. doi: 10.1016/j.ajhg.2009.06.008. Epub 2009 Jul 2.

PubMed [citation]

PMID:: 19576563
PMCID:: PMC2706970

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 (3)

Details of each submission

From GeneDx, SCV000577023.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in 21/279,222 (0.0075%) alleles in large population cohorts (gnomAD); RNA studies demonstrate homozygous individuals have a single smaller RNA band due to skipping of exon 6 and premature termination of the open reading frame, and heterozygous carriers have a mixture of RNA with normal and skipped products (Guernsey et al., 2009); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21431621, 18304158, 19648921, 19576563, 28294978, 26516448, 22052856, 24035636, 31589614)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001581116.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 266 of the PYCR1 protein (p.Arg266Gln). This variant is present in population databases (rs121918374, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive cutis laxa (PMID: 19576563, 19648921). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13190). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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 23, 2024

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