NM_013328.4(PYCR2):c.595C>T (p.Arg199Trp) AND Hypomyelinating leukodystrophy 10

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 19, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000240857.5

Allele description [Variation Report for NM_013328.4(PYCR2):c.595C>T (p.Arg199Trp)]

NM_013328.4(PYCR2):c.595C>T (p.Arg199Trp)

Gene:

PYCR2:pyrroline-5-carboxylate reductase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q42.12

Genomic location:

Preferred name:

NM_013328.4(PYCR2):c.595C>T (p.Arg199Trp)

HGVS:

NC_000001.11:g.225921590G>A
NG_044963.1:g.7751C>T
NM_001271681.2:c.373C>T
NM_013328.4:c.595C>TMANE SELECT
NP_001258610.1:p.Arg125Trp
NP_037460.2:p.Arg199Trp
NC_000001.10:g.226109290G>A
NM_013328.3:c.595C>T

Protein change:

R125W; ARG199TRP

Links:

OMIM: 616406.0004; dbSNP: rs758595075

NCBI 1000 Genomes Browser:

rs758595075

Molecular consequence:

NM_001271681.2:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013328.4:c.595C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypomyelinating leukodystrophy 10
Identifiers:: MONDO: MONDO:0014632; MedGen: C4225332; OMIM: 616420

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000299342	OMIM	no assertion criteria provided	Pathogenic (Sep 16, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002024777	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 19, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000299342

OMIM

no assertion criteria provided

Pathogenic
(Sep 16, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002024777

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 19, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.

Zaki MS, Bhat G, Sultan T, Issa M, Jung HJ, Dikoglu E, Selim L, G Mahmoud I, Abdel-Hamid MS, Abdel-Salam G, Marin-Valencia I, Gleeson JG.

Ann Neurol. 2016 Jul;80(1):59-70. doi: 10.1002/ana.24678. Epub 2016 Jun 1.

PubMed [citation]

PMID:: 27130255
PMCID:: PMC4938747

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000299342.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 unrelated children, born of consanguineous Egyptian parents, with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.595G-A transition in the PYCR2 gene, resulting in an arg199-to-trp (R199W) substitution at a highly conserved residue in the dimerization domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutations were filtered against the ExAC database and an in-house exome database of 5,000 individuals. One patient had 2 older deceased sibs with a similar disorder. In vitro functional expression studies showed that the mutant protein had reduced coprecipitation with the wildtype protein compared to controls, suggesting that the mutation impaired protein multimerization.

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

From Revvity Omics, Revvity, SCV002024777.3

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

#	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: Mar 16, 2024

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