NM_007144.3(PCGF2):c.194C>T (p.Pro65Leu) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 4, 2023
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:: RCV001580544.7

Allele description

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001817851	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 13, 2023)	germline	clinical testing	Citation Link,
SCV003441881	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30343942, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001817851

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 13, 2023)

germline

clinical testing

Citation Link,

SCV003441881

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 4, 2023)

germline

clinical testing

PubMed (2)
[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	unknown	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	clinical testing

Citations

PubMed

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001817851.2

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

Description

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: 30343942, 28628100, 28867141, 28135719, 31278258, 27535533, 31785789, 34750959, 25533962)

#	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, SCV003441881.2

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 65 of the PCGF2 protein (p.Pro65Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Turnpenny-Fry syndrome (PMID: 30343942). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 619193). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCGF2 protein function with a negative predictive value of 80%. 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 29, 2024

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