The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000804273 / PMID: 30426380). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_001031710.3(KLHL7):c.1051C>T (p.Arg351Ter)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001031710.3(KLHL7):c.1051C>T (p.Arg351Ter)
Variation ID: 804273 Accession: VCV000804273.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p15.3 7: 23165812 (GRCh38) [ NCBI UCSC ] 7: 23205431 (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 13, 2020 Oct 20, 2024 Mar 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001031710.3:c.1051C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026880.2:p.Arg351Ter nonsense NM_018846.5:c.907C>T NP_061334.4:p.Arg303Ter nonsense NR_033328.2:n.1424C>T non-coding transcript variant NC_000007.14:g.23165812C>T NC_000007.13:g.23205431C>T NG_016983.2:g.65079C>T - Protein change
- R351*, R303*
- Other names
- -
- Canonical SPDI
- NC_000007.14:23165811:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| KLHL7 | - | - |
GRCh38 GRCh37 |
357 | 393 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Sep 1, 2022 | RCV000991230.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2024 | RCV001382705.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002274113.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental delay
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559135.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PERCHING syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573364.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000804273 / PMID: 30426380). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Intellectual disability (present) , Arthrogryposis multiplex congenita (present) , Fetal growth restriction (present) , Breathing dysregulation (present) , Ulnar deviation of the hand (present) , … (more)
Intellectual disability (present) , Arthrogryposis multiplex congenita (present) , Fetal growth restriction (present) , Breathing dysregulation (present) , Ulnar deviation of the hand (present) , Camptodactyly (present) , Microcephaly (present) , Sloping forehead (present) , Micrognathia (present) , Narrow mouth (present) , High palate (present) , Short nose (present) , Long eyelashes (present) , Proximal placement of thumb (present) , Anterior creases of earlobe (present) , Short neck (present) , Long philtrum (present) (less)
|
|
|
Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581607.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with autosomal recessive KLHL7-related conditions (PMID: 30426380, 30997404). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 804273). This variant is present in population databases (rs746612410, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Arg351*) in the KLHL7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KLHL7 are known to be pathogenic (PMID: 27392078, 30426380). (less)
|
|
|
Pathogenic
(Mar 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005327550.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31230720, 30997404, 30426380, 29074562) (less)
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004032727.11
First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024 |
Comment:
KLHL7: PVS1, PM2, PM3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 09, 2020)
|
no assertion criteria provided
Method: literature only
|
PERCHING SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001142626.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment on evidence:
In 2 sibs, aged 19 and 22 years and born of unrelated parents, with PERCHING syndrome (617055), Bruel et al. (2017) identified a homozygous mutation … (more)
In 2 sibs, aged 19 and 22 years and born of unrelated parents, with PERCHING syndrome (617055), Bruel et al. (2017) identified a homozygous mutation (NM_018846.4) in the KLHL7 gene, resulting in an arg351-to-ter (R351X) substitution in the Kelch-repeat domain. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in public genomic databases, including ExAC. Functional studies of the variant and studies of patient cells were not performed. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
PERCHING syndrome
This variant was identified in an
(more...)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001167486.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Number of individuals with the variant: 4
Family history: yes
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with autosomal recessive KLHL7-related conditions (PMID: 30426380, 30997404). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 804273). This variant is present in population databases (rs746612410, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Arg351*) in the KLHL7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KLHL7 are known to be pathogenic (PMID: 27392078, 30426380).
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31230720, 30997404, 30426380, 29074562)
Comment:
KLHL7: PVS1, PM2, PM3
Comment on condition
This variant was identified in an individual with arthrogryposis and multiple system disorder
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:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000804273 / PMID: 30426380). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with autosomal recessive KLHL7-related conditions (PMID: 30426380, 30997404). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 804273). This variant is present in population databases (rs746612410, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Arg351*) in the KLHL7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KLHL7 are known to be pathogenic (PMID: 27392078, 30426380).
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31230720, 30997404, 30426380, 29074562)
Comment:
KLHL7: PVS1, PM2, PM3
Comment on condition
This variant was identified in an individual with arthrogryposis and multiple system disorder
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| New macular findings in individuals with biallelic KLHL7 gene mutation. | Heng LZ | BMJ open ophthalmology | 2019 | PMID: 30997404 |
| Comparison of clinical parameters with whole exome sequencing analysis results of autosomal recessive patients; a center experience. | Elmas M | Molecular biology reports | 2019 | PMID: 30426380 |
| Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype. | Bruel AL | Journal of medical genetics | 2017 | PMID: 29074562 |
| Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. | Angius A | American journal of human genetics | 2016 | PMID: 27392078 |
Text-mined citations for rs746612410 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.