VCV000279774.12 - ClinVar

NM_000390.4(CHM):c.757C>T (p.Arg253Ter)

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000390.4(CHM):c.757C>T (p.Arg253Ter)

Variation ID: 279774 Accession: VCV000279774.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq21.2 X: 85958923 (GRCh38) [ NCBI UCSC ] X: 85213928 (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	Dec 28, 2024	Jan 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000390.4:c.757C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000381.1:p.Arg253Ter	nonsense
NM_000390.3:c.757C>T
NM_001320959.1:c.313C>T	NP_001307888.1:p.Arg105Ter	nonsense
NM_001362517.1:c.313C>T	NP_001349446.1:p.Arg105Ter	nonsense
NM_001362518.2:c.313C>T	NP_001349447.1:p.Arg105Ter	nonsense
NM_001362519.1:c.313C>T	NP_001349448.1:p.Arg105Ter	nonsense
NC_000023.11:g.85958923G>A
NC_000023.10:g.85213928G>A
NG_009874.2:g.93640C>T
LRG_699:g.93640C>T
LRG_699t1:c.757C>T

... more HGVS ... less HGVS

Protein change

R253*, R105*

Other names

Canonical SPDI

NC_000023.11:85958922: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

ClinGen: CA10603741 dbSNP: rs886041178 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.
CHM		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	838	1072

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 provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 3, 2024	RCV000265578.9
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787565.1
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV003888669.2
CHM-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 27, 2024	RCV004755834.1

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.
Pathogenic (Sep 27, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329292.6 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: The R253X nonsense variant in the CHM gene has been reported previously in association with choroideremia (McTaggart et al. 2002; Francis et al. 2005; Fujiki … (more) The R253X nonsense variant in the CHM gene has been reported previously in association with choroideremia (McTaggart et al. 2002; Francis et al. 2005; Fujiki et al. 1999; Esposito et al. 2011; Hayakawa et al. 1999; van den Hurk et al. 2003; Jacobson et al. 2006). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. (less)
Pathogenic (Jan 03, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001384350.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 9067750‚ 23811034‚ 19422966‚ 28559085 Comment: This sequence change creates a premature translational stop signal (p.Arg253) in the CHM gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg253) in the CHM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHM are known to be pathogenic (PMID: 9067750, 23811034). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with choroideremia (PMID: 19422966, 28559085). ClinVar contains an entry for this variant (Variation ID: 279774). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004707162.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Pathogenic (Jan 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005068638.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (13) PubMed: 10420196‚ 19422966‚ 25525159‚ 28752371‚ 28559085‚ 29847639‚ 30297895‚ 30718709‚ 31416074‚ 31922496‚ 32985515‚ 33090715‚ 36460718
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926542.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Sep 27, 2024)	no assertion criteria provided Method: clinical testing	CHM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360341.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CHM c.757C>T variant is predicted to result in premature protein termination (p.Arg253). This variant has been reported as causative for choroideremia (see for examples … (more) The CHM c.757C>T variant is predicted to result in premature protein termination (p.Arg253). This variant has been reported as causative for choroideremia (see for examples van den Hurk et al. 2003. PubMed ID: 12827496; MacDonald et al. 2009. PubMed ID: 19422966; Hayakawa et al. 1999. PubMed ID: 10420196). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHM are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/279774). Given all the evidence, we interpret c.757C>T (p.Arg253*) as pathogenic. (less)

Comment:

The R253X nonsense variant in the CHM gene has been reported previously in association with choroideremia (McTaggart et al. 2002; Francis et al. 2005; Fujiki et al. 1999; Esposito et al. 2011; Hayakawa et al. 1999; van den Hurk et al. 2003; Jacobson et al. 2006). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.

Comment:

This sequence change creates a premature translational stop signal (p.Arg253*) in the CHM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHM are known to be pathogenic (PMID: 9067750, 23811034). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with choroideremia (PMID: 19422966, 28559085). ClinVar contains an entry for this variant (Variation ID: 279774). For these reasons, this variant has been classified as Pathogenic.

Comment:

The CHM c.757C>T variant is predicted to result in premature protein termination (p.Arg253*). This variant has been reported as causative for choroideremia (see for examples van den Hurk et al. 2003. PubMed ID: 12827496; MacDonald et al. 2009. PubMed ID: 19422966; Hayakawa et al. 1999. PubMed ID: 10420196). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHM are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/279774). Given all the evidence, we interpret c.757C>T (p.Arg253*) as 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
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non-syndromic inherited retinal dystrophies.	Liu X	Clinical & experimental ophthalmology	2021	PMID: 33090715
Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families.	Hayashi T	Scientific reports	2020	PMID: 32985515
CLINICAL CHARACTERISTICS AND MOLECULAR GENETIC ANALYSIS OF A COHORT OF CHINESE PATIENTS WITH CHOROIDEREMIA.	Han X	Retina (Philadelphia, Pa.)	2020	PMID: 31922496
Peculiar Clinical Findings in Young Choroideremia Patients: A Retrospective Case Review.	Mucciolo DP	Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde	2019	PMID: 31416074
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia.	Xue K	Nature medicine	2018	PMID: 30297895
Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families.	Martin-Merida I	Investigative ophthalmology & visual science	2018	PMID: 29847639
Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers.	Murro V	Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie	2017	PMID: 28752371
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
A clinical molecular genetic service for United Kingdom families with choroideraemia.	Ramsden SC	European journal of medical genetics	2013	PMID: 23811034
Choroideremia: new findings from ocular pathology and review of recent literature.	MacDonald IM	Survey of ophthalmology	2009	PMID: 19422966
Visual impairment and REP-1 gene mutations in Japanese choroideremia patients.	Hayakawa M	Ophthalmic genetics	1999	PMID: 10420196
Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene.	van den Hurk JA	Human mutation	1997	PMID: 9067750
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Text-mined citations for rs886041178 ...

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 Dec 28, 2024

ClinVar Genomic variation as it relates to human health

NM_000390.4(CHM):c.757C>T (p.Arg253Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041178 ...