ClinVar Genomic variation as it relates to human health
NM_017777.4(MKS1):c.857A>G (p.Asp286Gly)
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.857A>G (p.Asp286Gly)
Variation ID: 445724 Accession: VCV000445724.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q22 17: 58212983 (GRCh38) [ NCBI UCSC ] 17: 56290344 (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 Nov 5, 2017 Oct 8, 2024 May 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017777.4:c.857A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060247.2:p.Asp286Gly missense NM_001321268.2:c.248A>G NP_001308197.1:p.Asp83Gly missense NM_001321269.2:c.857A>G NP_001308198.1:p.Asp286Gly missense NM_001330397.2:c.857A>G NP_001317326.1:p.Asp286Gly missense NC_000017.11:g.58212983T>C NC_000017.10:g.56290344T>C NG_013032.1:g.11623A>G LRG_687:g.11623A>G LRG_687t1:c.857A>G LRG_687p1:p.Asp286Gly - Protein change
- D286G, D83G
- Other names
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- Canonical SPDI
- NC_000017.11:58212982:T:C
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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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0.00060 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00051
Exome Aggregation Consortium (ExAC) 0.00053
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00083
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00096
Trans-Omics for Precision Medicine (TOPMed) 0.00096
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
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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 |
947 | 1025 |
Conditions - Germline
Condition
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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. |
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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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May 15, 2023 | RCV000514949.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2022 | RCV000690393.6 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2022 | RCV000664898.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000989953.6 | |
Uncertain significance (2) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001126360.6 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jun 7, 2022 | RCV002271519.4 | |
Uncertain significance (1) |
no assertion criteria provided
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Aug 8, 2024 | RCV004527618.2 |
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. |
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Uncertain significance
(Sep 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610371.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Uncertain significance
(Jan 03, 2017)
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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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Counsyl
Accession: SCV000788928.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(May 08, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000854879.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
Number of individuals with the variant: 8
Sex: mixed
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001140699.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Meckel syndrome, type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001285541.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 13
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001285542.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555728.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: MKS1 c.857A>G (p.Asp286Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: MKS1 c.857A>G (p.Asp286Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 249582 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 (0.00051 vs 0.0011), allowing no conclusion about variant significance. c.857A>G has been reported in the literature in individuals affected with Meckel Syndrome Type 1 or related disorders. These reports do not provide unequivocal conclusions about association of the variant with Meckel Syndrome Type 1. At least one publication reports experimental evidence evaluating an impact on protein function and suggested that this variant was hypomorphic (Leitch_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, VUS n=8). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 13
Joubert syndrome 28 Meckel syndrome, type 1
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV002764340.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Clinical Features:
Hepatic steatosis (present) , Type 2 diabetes mellitus (present) , Hyperlipidemia (present)
Secondary finding: no
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Uncertain significance
(Feb 17, 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: SCV002786590.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial aplasia of the vermis
Meckel-Gruber syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000818077.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 286 of the MKS1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 286 of the MKS1 protein (p.Asp286Gly). This variant is present in population databases (rs151023718, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ciliopathies (PMID: 18327255, 21068128, 21258341, 28224992). ClinVar contains an entry for this variant (Variation ID: 445724). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MKS1 function (PMID: 18327255). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. (less)
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Uncertain significance
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001822451.4
First in ClinVar: Sep 08, 2021 Last updated: May 27, 2023 |
Comment:
Reported in the heterozygous state in patients with nephronophthisis, Bardet-Biedl syndrome, and a developmental eye defect with no second MKS1 variant reported (Leitch et al., … (more)
Reported in the heterozygous state in patients with nephronophthisis, Bardet-Biedl syndrome, and a developmental eye defect with no second MKS1 variant reported (Leitch et al., 2008; Otto et al., 2011; Haer-Wigman et al., 2017); Reported in the heterozygous state in a patient with Bardet-Biedl who was also heterozygous for a variant in the RPGRIP1L gene (Khanna et al., 2009); Functional studies indicate this variant has a moderate effect on protein function and is a hypomorphic variant (Leitch et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25966130, 19430481, 28224992, 21068128, 21258341, 30718709, 31139930, 18327255, 34426522, 34573333, 32483926) (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005192977.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
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Likely pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926866.2 First in ClinVar: Nov 05, 2017 Last updated: Sep 03, 2023 |
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Uncertain significance
(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: SCV001455376.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553176.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MKS1 p.Asp83Gly variant was identified in multiple individuals with ciliopathies or neural tube defects as a heterozygous variant, however a second pathogenic variant was … (more)
The MKS1 p.Asp83Gly variant was identified in multiple individuals with ciliopathies or neural tube defects as a heterozygous variant, however a second pathogenic variant was not found in these cases (Renard_2019_PMID:31139930, Davis_2011_PMID:21258341, Otto_2011_PMID:21068128). A functional study conducted on this variant suggested this variant may impact protein function (Leitch_2008_PMID:18327255). The variant was identified in dbSNP (ID: rs151023718) and ClinVar (classified as uncertain significance by Invitae, Counsyl, and three other laboratories, and as as likely pathogenic by Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet). The variant was identified in control databases in 144 of 280976 chromosomes at a frequency of 0.0005125 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 128 of 128714 chromosomes (freq: 0.000995), Other in 3 of 7152 chromosomes (freq: 0.00042), African in 6 of 24200 chromosomes (freq: 0.000248), European (Finnish) in 4 of 25036 chromosomes (freq: 0.00016), Ashkenazi Jewish in 1 of 10362 chromosomes (freq: 0.000097) and Latino in 2 of 35376 chromosomes (freq: 0.000057), but was not observed in the East Asian or South Asian populations. The p.Asp83 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Asp83Gly variant occurs in the second last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the loss of the canonical 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(Dec 02, 2022)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV003839718.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the MKS1 gene demonstrated a sequence change, c.857A>G, in exon 8 that results in an amino acid change, p.Asp286Gly. This sequence … (more)
DNA sequence analysis of the MKS1 gene demonstrated a sequence change, c.857A>G, in exon 8 that results in an amino acid change, p.Asp286Gly. This sequence change does not appear to have been previously described in individuals with nephronophthisis, Bardet-Biedl syndrome, Leber Congenital Amaurosis and a developmental eye defect (PMID:18327255,27353947,28224992,19430481). Experimental studies indicate this variant has a moderate effect on protein function (PMID:18327255). This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European subpopulation (dbSNP rs151023718). The p.Asp286Gly change affects a highly conserved amino acid residue located in a domain of the MKS1 protein that is not known to be functional. The p.Asp286Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp286Gly change remains unknown at this time. (less)
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Uncertain significance
(Aug 08, 2024)
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no assertion criteria provided
Method: clinical testing
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MKS1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004107145.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The MKS1 c.857A>G variant is predicted to result in the amino acid substitution p.Asp286Gly. This variant has previously been identified in several individuals affected with … (more)
The MKS1 c.857A>G variant is predicted to result in the amino acid substitution p.Asp286Gly. This variant has previously been identified in several individuals affected with ciliopathies (see, for example, Leitch et al. 2008. PubMed ID: 18327255; Otto et al. 2010. PubMed ID: 21068128; Davis et al. 2011. PubMed ID: 21258341; Haer-Wigman et al. 2017. PubMed ID: 28224992; Table S5, Martin-Merida et al. 2019. PubMed ID: 30902645). However, a second likely causative variant was not found in MKS1 in these cases. This variant has also been reported in a patient with hereditary vison loss (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926). Mutant rescue experiments in zebrafish embryos with p.Asp286Gly resulted in only partial rescue, suggesting that this variant is a hypomorph in this artificial system (Leitch et al. 2008. PubMed ID: 18327255). However, the clinical significance of this rescue experiment is unclear. Splice-site prediction programs suggest that the c.857A>G variant may interfere with normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant is reported in 0.099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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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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Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
Diagnostic exome sequencing in 266 Dutch patients with visual impairment. | Haer-Wigman L | European journal of human genetics : EJHG | 2017 | PMID: 28224992 |
Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies. | Tiwari A | Scientific reports | 2016 | PMID: 27353947 |
TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. | Davis EE | Nature genetics | 2011 | PMID: 21258341 |
Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy. | Otto EA | Journal of medical genetics | 2011 | PMID: 21068128 |
A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. | Khanna H | Nature genetics | 2009 | PMID: 19430481 |
Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. | Leitch CC | Nature genetics | 2008 | PMID: 18327255 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MKS1 | - | - | - | - |
Text-mined citations for rs151023718 ...
HelpRecord last updated Oct 08, 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.