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NM_017777.4(MKS1):c.417G>A (p.Glu139=) AND Meckel-Gruber syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 31, 2017
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000605128.4

Allele description [Variation Report for NM_017777.4(MKS1):c.417G>A (p.Glu139=)]

NM_017777.4(MKS1):c.417G>A (p.Glu139=)

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.417G>A (p.Glu139=)
HGVS:
  • NC_000017.11:g.58216088C>T
  • NG_013032.1:g.8518G>A
  • NM_001321268.2:c.-95G>A
  • NM_001321269.2:c.417G>A
  • NM_001330397.2:c.417G>A
  • NM_017777.4:c.417G>AMANE SELECT
  • NP_001308198.1:p.Glu139=
  • NP_001317326.1:p.Glu139=
  • NP_060247.2:p.Glu139=
  • NP_060247.2:p.Glu139=
  • LRG_687t1:c.417G>A
  • LRG_687t2:c.387G>A
  • LRG_687:g.8518G>A
  • LRG_687p1:p.Glu139=
  • LRG_687p2:p.Glu129=
  • NC_000017.10:g.56293449C>T
  • NM_017777.3:c.417G>A
  • NM_017777.4:c.417G>A
  • p.Glu139Glu
Note:
NCBI staff reviewed the sequence information reported in PubMed 17377820 Fig. 1A to determine the location of this allele on the current reference sequence.
Nucleotide change:
417G-A
Links:
OMIM: 609883.0005; dbSNP: rs386834048
NCBI 1000 Genomes Browser:
rs386834048
Molecular consequence:
  • NM_001321268.2:c.-95G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001321269.2:c.417G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001330397.2:c.417G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_017777.4:c.417G>A - synonymous variant - [Sequence Ontology: SO:0001819]
Observations:
1

Condition(s)

Name:
Meckel-Gruber syndrome
Synonyms:
DYSENCEPHALIA SPLANCHNOCYSTICA; Gruber syndrome; Dysencephalia splachnocystica
Identifiers:
MONDO: MONDO:0018921; MedGen: C0265215; OMIM: PS249000

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000731819Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Jul 31, 2017) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Identification of deleterious synonymous variants in human genomes.

Buske OJ, Manickaraj A, Mital S, Ray PN, Brudno M.

Bioinformatics. 2013 Aug 1;29(15):1843-50. doi: 10.1093/bioinformatics/btt308. Epub 2013 Jun 4. Erratum in: Bioinformatics. 2015 Mar 1;31(5):799. doi: 10.1093/bioinformatics/btu765.

PubMed [citation]
PMID:
23736532

Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.

Consugar MB, Kubly VJ, Lager DJ, Hommerding CJ, Wong WC, Bakker E, Gattone VH 2nd, Torres VE, Breuning MH, Harris PC.

Hum Genet. 2007 Jun;121(5):591-9. Epub 2007 Mar 22.

PubMed [citation]
PMID:
17377820
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731819.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.Glu139Glu (NM_017777.3 c.417G>A) variant in MKS1 has been reported in 8 co mpound heterozygous individuals with Meckel syndrome and 1 compound heterozygous individual with Joubert syndrome (Consugar 2007, Khaddour 2007, Frank 2007, Tal lila 2009, Bachmann-Gagescu 2015). This variant is located in the last base of t he exon, which is part of the 5? splice region, and has been demonstrated to imp act splicing in patient cells (Consugar 2007). It has been identified in 31/126, 722 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs386834048, rs370514840). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency. Biallelic loss of function of the MKS1 g ene is associated with Meckel syndrome and Joubert syndrome. In summary, the p. Glu139Glu variant is likely pathogenic for Meckel syndrome in an autosomal reces sive manner based on its occurrence in affected individuals and demonstrated imp act on splicing.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Nov 3, 2024