NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 12, 2024
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:: RCV000153040.42

Allele description [Variation Report for NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile)]

NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile)

Gene:

CNGB1:cyclic nucleotide gated channel subunit beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q21

Genomic location:

Preferred name:

NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile)

HGVS:

NC_000016.10:g.57901371T>A
NG_016351.1:g.74746A>T
NM_001286130.2:c.2939A>T
NM_001297.5:c.2957A>TMANE SELECT
NP_001273059.1:p.Asn980Ile
NP_001288.3:p.Asn986Ile
NP_001288.3:p.Asn986Ile
NC_000016.9:g.57935275T>A
NM_001297.4:c.2957A>T
p.(Asn986Ile)

Protein change:

N980I

Links:

dbSNP: rs201162411

NCBI 1000 Genomes Browser:

rs201162411

Molecular consequence:

NM_001286130.2:c.2939A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001297.5:c.2957A>T - 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
SCV001207500	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21147909, 28041643, 28056120, 28559085, 29912909, 28492532
SCV001245983	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2020)	germline	clinical testing	Citation Link,
SCV001480162	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001813463	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 29, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes.

Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SA, Alkuraya FS.

Genome Res. 2013 Feb;23(2):236-47. doi: 10.1101/gr.144105.112. Epub 2012 Oct 26.

PubMed [citation]

PMID:: 23105016
PMCID:: PMC3561865

Molecular diagnosis for heterogeneous genetic diseases with targeted high-throughput DNA sequencing applied to retinitis pigmentosa.

Simpson DA, Clark GR, Alexander S, Silvestri G, Willoughby CE.

J Med Genet. 2011 Mar;48(3):145-51. doi: 10.1136/jmg.2010.083568. Epub 2010 Dec 8.

PubMed [citation]

PMID:: 21147909

See all PubMed Citations (8)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000202494.7

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

#	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		1	not provided	not provided	not provided

From Invitae, SCV001207500.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 986 of the CNGB1 protein (p.Asn986Ile). This variant is present in population databases (rs201162411, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 21147909, 28041643, 28056120, 28559085, 29912909). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 166891). 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 CNGB1 protein function with a positive 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

From CeGaT Center for Human Genetics Tuebingen, SCV001245983.20

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

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001480162.1

#	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	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001813463.4

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

Description

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: 23105016, 32483926, 32531858, 28056120, 26355662, 21147909, 29912909, 23977260, 24015210, 29068140, 28559085, 28041643, 30718709, 31725169, 31456290, 33465333, 34426522, 31570810, 33576794, 33847019, 32037395)

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000202494	Eurofins Ntd Llc (ga)	flagged submission Reason: Older claim that does not account for recent evidence Notes: None (EGL Classification Definitions 2015)	Uncertain significance (Apr 27, 2014)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21147909, 23105016 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000202494

Eurofins Ntd Llc (ga)

flagged submission

Reason: Older claim that does not account for recent evidence

Notes: None

(EGL Classification Definitions 2015)

Uncertain significance
(Apr 27, 2014)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Last Updated: Apr 20, 2024

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Relating variation to medicine