ClinVar Genomic variation as it relates to human health
NM_017777.4(MKS1):c.1450_1453dup (p.Thr485fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017777.4(MKS1):c.1450_1453dup (p.Thr485fs)
Variation ID: 56617 Accession: VCV000056617.17
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 17q22 17: 58206501-58206502 (GRCh38) [ NCBI UCSC ] 17: 56283862-56283863 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 24, 2013 Feb 28, 2024 Dec 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017777.4:c.1450_1453dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060247.2:p.Thr485fs frameshift NM_001321268.2:c.841_844dup NP_001308197.1:p.Thr282fs frameshift NM_001321269.2:c.1408-125_1408-122dup intron variant NM_001330397.2:c.1274-125_1274-122dup intron variant NM_017777.3:c.1450_1453dupGGCA NC_000017.11:g.58206504_58206507dup NC_000017.10:g.56283865_56283868dup NG_013020.1:g.18777_18780dup NG_013032.1:g.18101_18104dup LRG_687:g.18101_18104dup LRG_687t1:c.1450_1453dup LRG_687p1:p.Thr485fs - Protein change
- T282fs, T485fs
- Other names
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- Canonical SPDI
- NC_000017.11:58206501:TGCCTG:TGCCTGCCTG
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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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. |
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MKS1 | - | - |
GRCh38 GRCh37 |
938 | 1014 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
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Sep 16, 2020 | RCV000050030.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2016 | RCV000230084.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000340753.5 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 5, 2016 | RCV000984283.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 13, 2023 | RCV000984282.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 10, 2023 | RCV001063563.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2021 | RCV001781381.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2022 | RCV002496727.1 |
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. |
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Pathogenic
(Feb 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial aplasia of the vermis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000290334.2
First in ClinVar: Jul 01, 2016 Last updated: Jul 01, 2016 |
Comment:
This sequence change inserts 4 nucleotides in exon 16 of the MKS1 mRNA (c.1450_1453dupGGCA), causing a frameshift at codon 485. This creates a premature translational … (more)
This sequence change inserts 4 nucleotides in exon 16 of the MKS1 mRNA (c.1450_1453dupGGCA), causing a frameshift at codon 485. This creates a premature translational stop signal (p.Thr485Argfs*107) and is expected to result in an absent or disrupted protein product. Truncating variants in MKS1 are known to be pathogenic. This particular truncation has been reported in the homozygous state from an individual affected with Meckel Gruber syndrome in the literature (PMID: 17397051, 17185389). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108 in the literature. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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MKS1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000404278.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The MKS1 c.1450_1453dupGGCA (p.Thr485ArgfsTer107) variant, also known as c.1448_1451dupCAGG, results in a frameshift and is predicted to cause an elongation of the protein. Across a … (more)
The MKS1 c.1450_1453dupGGCA (p.Thr485ArgfsTer107) variant, also known as c.1448_1451dupCAGG, results in a frameshift and is predicted to cause an elongation of the protein. Across a selection of available literature, the p.Thr485ArgfsTer107 variant was identified in a homozygous state in four individuals with Meckel syndrome from consanguineous families of Pakistani origin (Dawe et al. 2007; Khaddour et al. 2007; Szymanska et al. 2012). The p.Thr485ArgfsTer107 variant has not been reported in any cases of Bardet-Biedl syndrome. The variant was absent from 96 healthy controls but is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. Dawe et al. (2007) conducted immunohistochemistry staining in kidney tissue from an affected individual carrying the p.Thr485ArgfsTer107 variant and demonstrated a lack of MKS1 protein compared to age-matched control tissue. Based on the evidence from the literature and potential impact of frameshift variants, the p.Thr485ArgfsTer107 variant is classified as likely pathogenic for MKS1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Mar 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Meckel syndrome, type 1
Bardet-Biedl syndrome 13 Joubert syndrome 28
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002812864.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 13
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
inherited
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Pediatrics Genetics, Post Graduate Institute of Medical Education and Research
Accession: SCV003804983.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
PVS1, PM2, PP5
Sex: male
Ethnicity/Population group: North India
Geographic origin: India
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Pathogenic
(Sep 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 13
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004194929.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024357.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial aplasia of the vermis
Meckel-Gruber syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001228414.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change results in a frameshift in the MKS1 gene (p.Thr485Argfs*107). While this is not anticipated to result in nonsense mediated decay, it is … (more)
This sequence change results in a frameshift in the MKS1 gene (p.Thr485Argfs*107). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the MKS1 protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs386834044, gnomAD 0.06%). This frameshift has been observed in individual(s) with Meckel Gruber syndrome (PMID: 17185389, 17397051). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108. ClinVar contains an entry for this variant (Variation ID: 56617). This variant results in an extension of the MKS1 protein. Other variant(s) that result in a similarly extended protein product (p.Arg510Profs*81) have been observed in individuals with MKS1-related disease (PMID: 26490104). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic. (less)
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Meckel syndrome type1
Affected status: not provided
Allele origin:
unknown
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082439.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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Likely pathogenic
(Dec 05, 2016)
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no assertion criteria provided
Method: clinical testing
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Meckel syndrome, type 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132431.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(Dec 05, 2016)
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no assertion criteria provided
Method: clinical testing
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Joubert syndrome 28
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132433.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(Dec 05, 2016)
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no assertion criteria provided
Method: clinical testing
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Bardet-Biedl syndrome 13
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132432.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Meckel syndrome type 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455366.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MKS1 regulates ciliary INPP5E levels in Joubert syndrome. | Slaats GG | Journal of medical genetics | 2016 | PMID: 26490104 |
Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies. | Szymanska K | Cilia | 2012 | PMID: 23351400 |
Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online. | Khaddour R | Human mutation | 2007 | PMID: 17397051 |
The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. | Dawe HR | Human molecular genetics | 2007 | PMID: 17185389 |
Text-mined citations for rs386834044 ...
HelpRecord last updated May 12, 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.