NM_006245.4(PPP2R5D):c.632A>C (p.Gln211Pro) AND Hogue-Janssens syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Sep 20, 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:: RCV001261947.5

Allele description [Variation Report for NM_006245.4(PPP2R5D):c.632A>C (p.Gln211Pro)]

NM_006245.4(PPP2R5D):c.632A>C (p.Gln211Pro)

Gene:

PPP2R5D:protein phosphatase 2 regulatory subunit B'delta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_006245.4(PPP2R5D):c.632A>C (p.Gln211Pro)

HGVS:

NC_000006.12:g.43007305A>C
NG_050636.1:g.27807A>C
NM_001270476.2:c.179A>C
NM_006245.4:c.632A>CMANE SELECT
NM_180976.3:c.536A>C
NM_180977.3:c.314A>C
NP_001257405.1:p.Gln60Pro
NP_006236.1:p.Gln211Pro
NP_851307.1:p.Gln179Pro
NP_851308.1:p.Gln105Pro
NC_000006.11:g.42975043A>C
NM_006245.3:c.632A>C

Protein change:

Q105P

Links:

dbSNP: rs1762136390

NCBI 1000 Genomes Browser:

rs1762136390

Molecular consequence:

NM_001270476.2:c.179A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006245.4:c.632A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_180976.3:c.536A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_180977.3:c.314A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hogue-Janssens syndrome 1
Synonyms:: Intellectual disability-macrocephaly-hypotonia-behavioral abnormalities syndrome; HOUGE-JANSSENS SYNDROME 1; INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 35
Identifiers:: MONDO: MONDO:0014602; MedGen: C5779996; Orphanet: 457279; OMIM: 616355

Recent activity

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PREDICTED: Mus musculus SPO11 initiator of meiotic double stranded breaks (Spo11...
PREDICTED: Mus musculus SPO11 initiator of meiotic double stranded breaks (Spo11), transcript variant X2, mRNA
gi|1720399363|ref|XM_006499618.4|

Nucleotide
Mus musculus CDC42 guanine nucleotide exchange factor (GEF) 9, mRNA (cDNA clone ...
Mus musculus CDC42 guanine nucleotide exchange factor (GEF) 9, mRNA (cDNA clone MGC:176347 IMAGE:9055998), complete cds
gi|223462787|gb|BC141385.1|

Nucleotide
Mus musculus ES cells cDNA, RIKEN full-length enriched library, clone:C330011D11...
Mus musculus ES cells cDNA, RIKEN full-length enriched library, clone:C330011D11 product:hypothetical protein, full insert sequence
gi|26100880|dbj|AK082765.1|

Nucleotide
Clypeobarbus congicus NADH dehydrogenase subunit 5 (ND5) gene, partial cds; mito...
Clypeobarbus congicus NADH dehydrogenase subunit 5 (ND5) gene, partial cds; mitochondrial
gi|763431186|gb|KP659449.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001439298	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 10, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001443621	GenomeConnect - Simons Searchlight	no assertion criteria provided	Pathogenic (Aug 13, 2018)	de novo	provider interpretation
SCV001445890	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001521017	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 5, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005046473	Center for Molecular Medicine, Children’s Hospital of Fudan University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 20, 2023)	unknown	clinical testing	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	2	not provided	not provided	2	not provided	clinical testing, provider interpretation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001439298.1

#	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 GenomeConnect - Simons Searchlight, SCV001443621.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	provider interpretation	not provided
2	not provided	1	not provided	not provided	provider interpretation	not provided

Description

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-08-13 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.

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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445890.1

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

Description

This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.632A>C (p.Gln211Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It localizes to the B56Î´ regulatory subunit in the PPP2R5D protein in close proximity to other previously reported Pathogenic variants (PMID: 26168268). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.632A>C (p.Gln211Pro) variant is classified as Pathogenic.

#	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 Baylor Genetics, SCV001521017.1

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

Description

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	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 Center for Molecular Medicine, Children’s Hospital of Fudan University, SCV005046473.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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