6-43007292-T-C

Variant names:

• chr6-43007292-T-C
• rs869320691
• NM_006245.4:c.619T>C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_006245.4(PPP2R5D):​c.619T>C​(p.Trp207Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.02

Genes affected

PPP2R5D (HGNC:9312): (protein phosphatase 2 regulatory subunit B'delta) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_006245.4 (PPP2R5D) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPP2R5D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 3.6476 (above the threshold of 3.09). Trascript score misZ: 4.9069 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, syndromic intellectual disability, Hogue-Janssens syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 6-43007292-T-C is Pathogenic according to our data. Variant chr6-43007292-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.619T>C	p.Trp207Arg	missense_variant	Exon 5 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.523T>C	p.Trp175Arg	missense_variant	Exon 5 of 16		NP_851307.1
PPP2R5D	NM_180977.3	c.301T>C	p.Trp101Arg	missense_variant	Exon 3 of 14		NP_851308.1
PPP2R5D	NM_001270476.2	c.166T>C	p.Trp56Arg	missense_variant	Exon 5 of 16		NP_001257405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.619T>C	p.Trp207Arg	missense_variant	Exon 5 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.523T>C	p.Trp175Arg	missense_variant	Exon 5 of 16	1		ENSP00000377669.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:6

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280435). A different missense change at the same codon (p.Trp207Cys) has been reported to be associated with PPP2R5D-related disorder (ClinVar ID: VCV001333678/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 12, 2023

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PPP2R5D c.619T>C; p.Trp207Arg variant (rs869320691) is reported in the literature as a de novo variant in large neurodevelopmental disorder or intellectual disability cohorts (Chen 2021, Lelieveld 2017, Turner 2019). This variant is also reported in ClinVar (Variation ID: 280435). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant resulting in the same amino acid change, c.619T>A; p.Trp207Arg, is reported in several patients affected with Hogue-Janssens syndrome, also as a de novo variant (Gilissen 2014, Houge 2015). Functional analyses of the p.Trp207Arg variant protein demonstrate impaired subunit binding (Houge 2015) and computational analyses predict that this variant is deleterious (REVEL: 0.795). Based on available information, the c.619T>C; p.Trp207Arg variant is considered to be pathogenic. References: Chen Y et al. Comprehensive genome sequencing analyses identify novel gene mutations and copy number variations associated with infant developmental delay or intellectual disability (DD/ID). Genes Dis. 2021 Dec 3;9(5):1166-1169. PMID: 35873028. Gilissen C et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014 Jul 17;511(7509):344-7. PMID: 24896178. Houge G et al. B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest. 2015 Aug 3;125(8):3051-62. PMID: 26168268. Lelieveld SH et al. Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes. Am J Hum Genet. 2017 Sep 7;101(3):478-484. PMID: 28867141. Turner TN et al. Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders. Am J Hum Genet. 2019 Dec 5;105(6):1274-1285. PMID: 31785789. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. While loss-of-function was demonstrated, the possibility of dominant-negative has not been excluded and is also a proposed mechanism (PMID: 32074998, 26168268). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Trp207Cys) and p.(Trp207Leu) were each seen in at least one de novo individual with PPP2R5D-related intelectual disability (DECIPHER, PMID:33628804). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many individuals with PPP2R5D-related intellectual disability (MIM#616355), including at least four de novo reports (ClinVar, DECIPHER, PMID: 24896178, 26168268). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 05, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-05 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

not provided Pathogenic:4

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a large cohort of individuals with intellectual disability and/or developmental delays who had de novo variants identified by exome trio analysis; however no case specific information was provided (Lelieveld et al., 2017); Same amino acid substitution caused by a different nucleotide change (c.619T>A) has been reported as a de novo variant in the published literature in association with intellectual disability (Gilissen et al., 2014; Houge et al., 2015; HGMD); Not observed 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: 34448180, 33106617, 28867141, 33726816, 31785789, 33628804, 32074998, 34228795) -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 207 of the PPP2R5D protein (p.Trp207Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP2R5D-related conditions (PMID: 24896178). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280435). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPP2R5D function (PMID: 26168268). This variant disrupts the p.Trp207 amino acid residue in PPP2R5D. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 23, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-13	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0026);.;.;.;
MVP		0.88
MPC		3.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320691; hg19: chr6-42975030;