VCV000045499.33 - ClinVar

NM_006393.3(NEBL):c.604G>A (p.Gly202Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(2); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006393.3(NEBL):c.604G>A (p.Gly202Arg)

Variation ID: 45499 Accession: VCV000045499.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p12.31 10: 20868744 (GRCh38) [ NCBI UCSC ] 10: 21157673 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 20, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006393.3:c.604G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006384.1:p.Gly202Arg	missense
NM_001173484.2:c.358-55804G>A		intron variant
NM_001377322.1:c.358-55804G>A		intron variant
NM_001377323.1:c.310-55804G>A		intron variant
NM_001377324.1:c.301-55804G>A		intron variant
NM_001377325.1:c.292-55804G>A		intron variant
NM_001377326.1:c.250-55804G>A		intron variant
NM_001377327.1:c.250-55804G>A		intron variant
NM_001377328.1:c.250-55804G>A		intron variant
NM_213569.2:c.358-55804G>A		intron variant
NC_000010.11:g.20868744C>T
NC_000010.10:g.21157673C>T
NG_017092.1:g.310444G>A
LRG_411:g.310444G>A
LRG_411t1:c.358-55804G>A
LRG_411t2:c.604G>A	LRG_411p2:p.Gly202Arg

... more HGVS ... less HGVS

Protein change

G202R

Other names

p.G202R:GGA>AGA

Canonical SPDI

NC_000010.11:20868743:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00140 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00125

1000 Genomes Project 0.00140

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00177

The Genome Aggregation Database (gnomAD), exomes 0.00208

The Genome Aggregation Database (gnomAD) 0.00210

Trans-Omics for Precision Medicine (TOPMed) 0.00212

Exome Aggregation Consortium (ExAC) 0.00213

Links

ClinGen: CA136450 dbSNP: rs137973321 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NEBL		No evidence available	No evidence available	GRCh38 GRCh37	1120	1174

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 5, 2020	RCV000038704.15
Primary dilated cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Jan 19, 2024	RCV001085554.8
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Aug 1, 2022	RCV000723614.21
NEBL-related disorder	Likely benign (1)	no assertion criteria provided	Mar 30, 2021	RCV003934929.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Aug 05, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062382.7 First in ClinVar: May 03, 2013 Last updated: May 29, 2021	Publications: PubMed (2) PubMed: 20951326‚ 23632046 Comment: The p.Gly202Arg variant in NEBL is classified as benign because it has been identified in 0.3% (24/7206) of Ashkenazi Jewish and in 0.2% (361/128806) of … (more) The p.Gly202Arg variant in NEBL is classified as benign because it has been identified in 0.3% (24/7206) of Ashkenazi Jewish and in 0.2% (361/128806) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. (less) Number of individuals with the variant: 6
Likely benign (Jan 13, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236092.11 First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019	Comment: Reported in one individual with adult-onset DCM, one individual with HCM, and one stillbirth case in published literature (Purevjav et al., 2010; Perrot et al., … (more) Reported in one individual with adult-onset DCM, one individual with HCM, and one stillbirth case in published literature (Purevjav et al., 2010; Perrot et al., 2016; Sahlin et al., 2019); however, no segregation studies were described; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 45499; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25987543, 23299917, 25353622, 27186169, 27171814, 27301361, 20951326, 27896284, 21430528, 28654958, 30615648, 23632046) (less)
Likely benign (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Primary dilated cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000563556.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Uncertain significance (May 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611493.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Aug 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004126536.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: NEBL: BP4, BS1, BS2 Number of individuals with the variant: 1
Uncertain significance (Jul 14, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331388.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 20951326‚ 23632046 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NEBL Number of individuals with the variant: 2 Sex: mixed
Likely benign (Mar 30, 2021)	no assertion criteria provided Method: clinical testing	NEBL-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004752357.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932407.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971783.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021

Comment:

The p.Gly202Arg variant in NEBL is classified as benign because it has been identified in 0.3% (24/7206) of Ashkenazi Jewish and in 0.2% (361/128806) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.

Comment:

Reported in one individual with adult-onset DCM, one individual with HCM, and one stillbirth case in published literature (Purevjav et al., 2010; Perrot et al., 2016; Sahlin et al., 2019); however, no segregation studies were described; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 45499; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25987543, 23299917, 25353622, 27186169, 27171814, 27301361, 20951326, 27896284, 21430528, 28654958, 30615648, 23632046)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases.	Tšuiko O	Human reproduction (Oxford, England)	2016	PMID: 27301361
Altered regional cardiac wall mechanics are associated with differential cardiomyocyte calcium handling due to nebulette mutations in preclinical inherited dilated cardiomyopathy.	Maiellaro-Rafferty K	Journal of molecular and cellular cardiology	2013	PMID: 23632046
Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.	Purevjav E	Journal of the American College of Cardiology	2010	PMID: 20951326
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NEBL	-	-	-	-

Text-mined citations for rs137973321 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_006393.3(NEBL):c.604G>A (p.Gly202Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137973321 ...