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NM_017777.4(MKS1):c.857A>G (p.Asp286Gly) AND not provided

Germline classification:
Uncertain significance (6 submissions)
Last evaluated:
May 15, 2023
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:
RCV000514949.12

Allele description [Variation Report for NM_017777.4(MKS1):c.857A>G (p.Asp286Gly)]

NM_017777.4(MKS1):c.857A>G (p.Asp286Gly)

Gene:
MKS1:MKS transition zone complex subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q22
Genomic location:
Preferred name:
NM_017777.4(MKS1):c.857A>G (p.Asp286Gly)
HGVS:
  • NC_000017.11:g.58212983T>C
  • NG_013032.1:g.11623A>G
  • NM_001321268.2:c.248A>G
  • NM_001321269.2:c.857A>G
  • NM_001330397.2:c.857A>G
  • NM_017777.4:c.857A>GMANE SELECT
  • NP_001308197.1:p.Asp83Gly
  • NP_001308198.1:p.Asp286Gly
  • NP_001317326.1:p.Asp286Gly
  • NP_060247.2:p.Asp286Gly
  • NP_060247.2:p.Asp286Gly
  • LRG_687t1:c.857A>G
  • LRG_687:g.11623A>G
  • LRG_687p1:p.Asp286Gly
  • NC_000017.10:g.56290344T>C
  • NM_017777.3:c.857A>G
Protein change:
D286G
Links:
dbSNP: rs151023718
NCBI 1000 Genomes Browser:
rs151023718
Molecular consequence:
  • NM_001321268.2:c.248A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321269.2:c.857A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330397.2:c.857A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_017777.4:c.857A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
8

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000610371Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Sep 11, 2017)
germlineclinical testing

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

SCV000854879Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL ClinVar v180209 classification definitions)
Uncertain significance
(May 8, 2018)
germlineclinical testing

Citation Link,

SCV000926866Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD
no assertion criteria provided
Likely pathogenic
(Apr 1, 2018)
unknownresearch

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

SCV001553176Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

SCV001822451GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Uncertain significance
(May 15, 2023)
germlineclinical testing

Citation Link,

SCV005192977Breakthrough Genomics, Breakthrough Genomics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significancegermlinenot provided

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown8not providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing, not provided
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing, research

Citations

PubMed

Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.

Jespersgaard C, Fang M, Bertelsen M, Dang X, Jensen H, Chen Y, Bech N, Dai L, Rosenberg T, Zhang J, Møller LB, Tümer Z, Brøndum-Nielsen K, Grønskov K.

Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.

PubMed [citation]
PMID:
30718709
PMCID:
PMC6362094

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 Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610371.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot provided0.000694not providednot provided

From Eurofins Ntd Llc (ga), SCV000854879.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided8not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided8not providednot providednot provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD, SCV000926866.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553176.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV001822451.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Breakthrough Genomics, Breakthrough Genomics, SCV005192977.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot provided PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024