VCV002169496.4 - ClinVar

NM_013328.4(PYCR2):c.596G>A (p.Arg199Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_013328.4(PYCR2):c.596G>A (p.Arg199Gln)

Variation ID: 2169496 Accession: VCV002169496.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q42.12 1: 225921589 (GRCh38) [ NCBI UCSC ] 1: 226109289 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 20, 2024	Oct 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_013328.4:c.596G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037460.2:p.Arg199Gln	missense
NM_001271681.2:c.374G>A	NP_001258610.1:p.Arg125Gln	missense
NM_013328.3:c.596G>A
NC_000001.11:g.225921589C>T
NC_000001.10:g.226109289C>T
NG_044963.1:g.7752G>A

... more HGVS ... less HGVS

Protein change

R125Q, R199Q

Other names

Canonical SPDI

NC_000001.11:225921588:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PYCR2		-	-	GRCh38 GRCh37	121	159

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Oct 24, 2023	RCV003084854.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 18, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003483361.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 27130255‚ 30829456 Comment: 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 … (more) 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. This variant disrupts the p.Arg199 amino acid residue in PYCR2. Other variant(s) that disrupt this residue have been observed in individuals with PYCR2-related conditions (PMID: 27130255, 30829456), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with leukodystrophy (PMID: 30829456). This variant is present in population databases (rs376952965, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 199 of the PYCR2 protein (p.Arg199Gln). (less)
Likely pathogenic (Oct 24, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004169118.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Previously identified in the homozygous state in an individual with hypomyelinating leukodystrophy 10; however, this individual was also heterozygous for a variant in another gene … (more) Previously identified in the homozygous state in an individual with hypomyelinating leukodystrophy 10; however, this individual was also heterozygous for a variant in another gene that may have contributed to the phenotype (PMID: 30829456); Not observed at significant frequency in large population cohorts (gnomAD); 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: 37563452, 30829456) (less)
Pathogenic (Nov 08, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: biparental	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031281.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)

Comment:

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. This variant disrupts the p.Arg199 amino acid residue in PYCR2. Other variant(s) that disrupt this residue have been observed in individuals with PYCR2-related conditions (PMID: 27130255, 30829456), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with leukodystrophy (PMID: 30829456). This variant is present in population databases (rs376952965, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 199 of the PYCR2 protein (p.Arg199Gln).

Comment:

Previously identified in the homozygous state in an individual with hypomyelinating leukodystrophy 10; however, this individual was also heterozygous for a variant in another gene that may have contributed to the phenotype (PMID: 30829456); Not observed at significant frequency in large population cohorts (gnomAD); 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: 37563452, 30829456)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Prolonged survival in a patient with a novel pyrroline-5-carboxylase reductase 2 genetic variant.	Spagnoli C	European journal of neurology	2019	PMID: 30829456
PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.	Zaki MS	Annals of neurology	2016	PMID: 27130255

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_013328.4(PYCR2):c.596G>A (p.Arg199Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...