NM_014704.4(CEP104):c.2737G>A (p.Gly913Arg) AND Joubert syndrome 25

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 24, 2022
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:: RCV000689733.6

Allele description [Variation Report for NM_014704.4(CEP104):c.2737G>A (p.Gly913Arg)]

NM_014704.4(CEP104):c.2737G>A (p.Gly913Arg)

Gene:

CEP104:centrosomal protein 104 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.32

Genomic location:

Preferred name:

NM_014704.4(CEP104):c.2737G>A (p.Gly913Arg)

Other names:

p.Gly913Arg

HGVS:

NC_000001.11:g.3815443C>T
NG_046726.1:g.46791G>A
NM_014704.4:c.2737G>AMANE SELECT
NP_055519.1:p.Gly913Arg
NC_000001.10:g.3732007C>T
NM_014704.3:c.2737G>A

Protein change:

G913R

Links:

dbSNP: rs201733773

NCBI 1000 Genomes Browser:

rs201733773

Molecular consequence:

NM_014704.4:c.2737G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Joubert syndrome 25 (JBTS25)
Identifiers:: MONDO: MONDO:0014770; MedGen: C4084842; Orphanet: 475; OMIM: 616781

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000817399	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004228237	Clinical Genomics Laboratory, Stanford Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000817399

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 24, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004228237

Clinical Genomics Laboratory, Stanford Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 27, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000817399.3

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 913 of the CEP104 protein (p.Gly913Arg). This variant is present in population databases (rs201733773, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CEP104-related conditions. ClinVar contains an entry for this variant (Variation ID: 569168). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Clinical Genomics Laboratory, Stanford Medicine, SCV004228237.1

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

Description

Heterozygous (maternally inherited)

Description

The p.Gly913Arg variant in the CEP104 gene has not been previously reported in association with disease. This variant was identified in trans with the c.2662+10A>T variant in this individual. The p.Gly913Arg variant has been identified in 62/281,042 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a high enough frequency to rule out pathogenicity. Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly913Arg variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4]

#	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

Last Updated: Sep 29, 2024

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