VCV001878640.5 - ClinVar

NM_018718.3(CEP41):c.856C>T (p.Arg286Ter)

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.

(3)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018718.3(CEP41):c.856C>T (p.Arg286Ter)

Variation ID: 1878640 Accession: VCV001878640.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q32.2 7: 130400156 (GRCh38) [ NCBI UCSC ] 7: 130039997 (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	Jan 21, 2023	May 1, 2024	Nov 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_018718.3:c.856C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_061188.1:p.Arg286Ter	nonsense
NM_001257158.2:c.757+551C>T		intron variant
NM_001257159.2:c.709+551C>T		intron variant
NM_018718.1:c.856C>T
NR_046443.2:n.830C>T		non-coding transcript variant
NC_000007.14:g.130400156G>A
NC_000007.13:g.130039997G>A
NG_032164.2:g.46055C>T

... more HGVS ... less HGVS

Protein change

R286*

Other names

Canonical SPDI

NC_000007.14:130400155:G:A

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.

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

Links

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.
CEP41		-	-	GRCh38 GRCh37	433	462

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.
Joubert syndrome 15	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 4, 2022	RCV002510731.4
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Oct 5, 2020	RCV002571602.2

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 15 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820281.1 First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023	Comment: The stop gained p.R286* in CEP41 (NM_018718.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. It … (more) The stop gained p.R286* in CEP41 (NM_018718.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. It is present in the penultimate exon but further downstream loss of function variants have been reported, thus supporting occurence of nonsense mediated decay. The p.R286* variant is observed in 1/18,394 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Hypotonia (present) , Ptosis (present) , Strabismus (present) , Global developmental delay (present)
Pathogenic (Nov 04, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Joubert syndrome 15 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004301522.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 22246503 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CEP41-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CEP41-related conditions. This variant is present in population databases (rs139123547, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg286*) in the CEP41 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP41 are known to be pathogenic (PMID: 22246503). (less)
Likely pathogenic (Oct 05, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003542058.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.856C>T (p.R286) alteration, located in coding exon 10 of the CEP41 gene, consists of a C to T substitution at nucleotide position 856. This … (more) The c.856C>T (p.R286) alteration, located in coding exon 10 of the CEP41 gene, consists of a C to T substitution at nucleotide position 856. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 286. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as likely pathogenic. (less)

Comment:

The stop gained p.R286* in CEP41 (NM_018718.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. It is present in the penultimate exon but further downstream loss of function variants have been reported, thus supporting occurence of nonsense mediated decay. The p.R286* variant is observed in 1/18,394 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CEP41-related conditions. This variant is present in population databases (rs139123547, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg286*) in the CEP41 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP41 are known to be pathogenic (PMID: 22246503).

Comment:

The c.856C>T (p.R286*) alteration, located in coding exon 10 of the CEP41 gene, consists of a C to T substitution at nucleotide position 856. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 286. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as likely pathogenic.

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
CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium.	Lee JE	Nature genetics	2012	PMID: 22246503

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_018718.3(CEP41):c.856C>T (p.Arg286Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...