NM_000283.4(PDE6B):c.2152G>A (p.Asp718Asn) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 15, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000297097.31

Allele description [Variation Report for NM_000283.4(PDE6B):c.2152G>A (p.Asp718Asn)]

NM_000283.4(PDE6B):c.2152G>A (p.Asp718Asn)

Gene:

PDE6B:phosphodiesterase 6B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000283.4(PDE6B):c.2152G>A (p.Asp718Asn)

HGVS:

NC_000004.12:g.664903G>A
NG_009839.1:g.44330G>A
NM_000283.4:c.2152G>AMANE SELECT
NM_001145291.2:c.2152G>A
NM_001145292.2:c.1315G>A
NM_001350154.3:c.1315G>A
NM_001350155.3:c.997G>A
NM_001379246.1:c.1315G>A
NM_001379247.1:c.1315G>A
NP_000274.2:p.Asp718Asn
NP_000274.3:p.Asp718Asn
NP_001138763.2:p.Asp718Asn
NP_001138764.2:p.Asp439Asn
NP_001337083.1:p.Asp439Asn
NP_001337084.1:p.Asp333Asn
NP_001366175.1:p.Asp439Asn
NP_001366176.1:p.Asp439Asn
NC_000004.11:g.658692G>A
NM_000283.3:c.2152G>A

Protein change:

D333N

Links:

dbSNP: rs150639487

NCBI 1000 Genomes Browser:

rs150639487

Molecular consequence:

NM_000283.4:c.2152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145291.2:c.2152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145292.2:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350154.3:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350155.3:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379246.1:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379247.1:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000340729	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Mar 23, 2016)	germline	clinical testing	Citation Link,
SCV001154144	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2019)	germline	clinical testing	Citation Link,
SCV001510447	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 34906470, 36819107, 30998820, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000340729

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Mar 23, 2016)

germline

clinical testing

Citation Link,

SCV001154144

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(May 1, 2019)

germline

clinical testing

Citation Link,

SCV001510447

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (4)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).

Zampaglione E, Maher M, Place EM, Wagner NE, DiTroia S, Chao KR, England E, Cmg B, Catomeris A, Nassiri S, Himes S, Pagliarulo J, Ferguson C, Galdikaité-Braziené E, Cole B, Pierce EA, Bujakowska KM.

Genet Med. 2022 Feb;24(2):332-343. doi: 10.1016/j.gim.2021.09.015. Epub 2021 Nov 30.

PubMed [citation]

PMID:: 34906470
PMCID:: PMC9200473

Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.

Panneman DM, Hitti-Malin RJ, Holtes LK, de Bruijn SE, Reurink J, Boonen EGM, Khan MI, Ali M, Andréasson S, De Baere E, Banfi S, Bauwens M, Ben-Yosef T, Bocquet B, De Bruyne M, de la Cerda B, Coppieters F, Farinelli P, Guignard T, Inglehearn CF, Karali M, Kjellström U, et al.

Front Cell Dev Biol. 2023;11:1112270. doi: 10.3389/fcell.2023.1112270.

PubMed [citation]

PMID:: 36819107
PMCID:: PMC9936074

See all PubMed Citations (4)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000340729.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	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		3	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001154144.27

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001510447.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 718 of the PDE6B protein (p.Asp718Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive PDE6B-related conditions (PMID: 34906470, 36819107; Invitae). ClinVar contains an entry for this variant (Variation ID: 287073). 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 expected to disrupt PDE6B protein function with a positive predictive value of 95%. This variant disrupts the p.Asp718 amino acid residue in PDE6B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30998820; Invitae). 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.

#	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: Oct 20, 2024

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