NM_007144.3(PCGF2):c.194C>T (p.Pro65Leu) AND Turnpenny-fry syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jul 16, 2019
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:: RCV000766184.7

Allele description [Variation Report for NM_007144.3(PCGF2):c.194C>T (p.Pro65Leu)]

NM_007144.3(PCGF2):c.194C>T (p.Pro65Leu)

Gene:

PCGF2:polycomb group ring finger 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q12

Genomic location:

Preferred name:

NM_007144.3(PCGF2):c.194C>T (p.Pro65Leu)

HGVS:

NC_000017.11:g.38739601G>A
NM_001369614.1:c.194C>T
NM_001369615.1:c.194C>T
NM_007144.3:c.194C>TMANE SELECT
NP_001356543.1:p.Pro65Leu
NP_001356544.1:p.Pro65Leu
NP_009075.1:p.Pro65Leu
NC_000017.10:g.36895854G>A
NM_007144.2:c.194C>T

Protein change:

P65L; PRO65LEU

Links:

OMIM: 600346.0001

Molecular consequence:

NM_001369614.1:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369615.1:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007144.3:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Turnpenny-fry syndrome
Synonyms:: NEUROCARDIOSKELETAL SYNDROME
Identifiers:: MONDO: MONDO:0032707; MedGen: C5193060; OMIM: 618371

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000897615	OMIM	no assertion criteria provided	Pathogenic (Sep 25, 2022)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15525528, 30343942
SCV000996450	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 16, 2019)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 30343942, 25741868
SCV001190251	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 13, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004171165	Institute of Human Genetics, University Hospital of Duesseldorf	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	not provided	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.

de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M, Koseki H, Brockdorff N.

Dev Cell. 2004 Nov;7(5):663-76.

PubMed [citation]

PMID:: 15525528

Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features.

Turnpenny PD, Wright MJ, Sloman M, Caswell R, van Essen AJ, Gerkes E, Pfundt R, White SM, Shaul-Lotan N, Carpenter L, Schaefer GB, Fryer A, Innes AM, Forbes KP, Chung WK, McLaughlin H, Henderson LB, Roberts AE, Heath KE, Paumard-Hernández B, Gener B; DDD study., et al.

Am J Hum Genet. 2018 Nov 1;103(5):786-793. doi: 10.1016/j.ajhg.2018.09.012. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2018 Dec 6;103(6):1054-1055. doi: 10.1016/j.ajhg.2018.11.009.

PubMed [citation]

PMID:: 30343942
PMCID:: PMC6218713

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000897615.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 unrelated children with Turnpenny-Fry syndrome (TPFS; 618371), the Deciphering Developmental Disorders Study (2015) identified heterozygosity for a G-to-A transition (chr17.36,895,854G-A, GRCh37) in the PCGF2 gene, resulting in a pro65-to-leu (P65L) substitution. The mutation arose de novo in both patients. Functional studies were not reported.

In 9 unrelated children with Turnpenny-Fry syndrome, Turnpenny et al. (2018) identified heterozygosity for a c.194C-T transition in the PCGF2 gene, resulting in the previously reported pro65-to-leu substitution at a highly conserved residue located just after the N-terminal RING finger motif. In 8 of the patients, the mutation arose de novo; however, in a 9-year-old girl (patient 11), the mutation was inherited from her asymptomatic mother, who was found to be mosaic (21% in blood DNA). Functional studies were not reported.

#	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 SIB Swiss Institute of Bioinformatics, SCV000996450.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as a Likely pathogenic for Turnpenny-Fry syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PS4-Moderate, PM6.

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

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001190251.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University Hospital of Duesseldorf, SCV004171165.1

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

#	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

Last Updated: Oct 8, 2024

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