NM_006907.4(PYCR1):c.797+2T>C AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 1, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV001816216.23

Allele description [Variation Report for NM_006907.4(PYCR1):c.797+2T>C]

NM_006907.4(PYCR1):c.797+2T>C

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.797+2T>C

HGVS:

NC_000017.11:g.81934324A>G
NG_023032.1:g.7769T>C
NG_023032.2:g.7976T>C
NM_001282279.2:c.704+2T>C
NM_001282280.2:c.797+2T>C
NM_001282281.2:c.878+2T>C
NM_001330523.2:c.633+329T>C
NM_006907.3:c.797+2T>C
NM_006907.4:c.797+2T>CMANE SELECT
NM_153824.3:c.797+2T>C
NC_000017.10:g.79892200A>G

Links:

dbSNP: rs768235246

NCBI 1000 Genomes Browser:

rs768235246

Molecular consequence:

NM_001330523.2:c.633+329T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001282279.2:c.704+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001282280.2:c.797+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001282281.2:c.878+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_006907.4:c.797+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_153824.3:c.797+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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uncharacterized protein PTSG_05291 [Salpingoeca rosetta]
uncharacterized protein PTSG_05291 [Salpingoeca rosetta]
gi|514692583|ref|XP_004993864.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002063667	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Oct 1, 2021)	germline	clinical testing	Citation Link,
SCV002308342	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 28, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19648921, 17576681, 9536098, 28454995, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002063667

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Oct 1, 2021)

germline

clinical testing

Citation Link,

SCV002308342

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 28, 2021)

germline

clinical testing

PubMed (5)
[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	1	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

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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (5)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV002063667.19

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002308342.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 6 of the PYCR1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs768235246, ExAC 0.002%). Disruption of this splice site has been observed in individual(s) with cutis laxa (PMID: 19648921). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PYCR1 protein in which other variant(s) (p.Lys289Arg) have been observed in individuals with PYCR1-related conditions (PMID: 28454995). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.

#	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: Oct 13, 2024

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