NM_017777.4(MKS1):c.763G>C (p.Gly255Arg) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 11, 2023
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:: RCV000695711.4

Allele description [Variation Report for NM_017777.4(MKS1):c.763G>C (p.Gly255Arg)]

NM_017777.4(MKS1):c.763G>C (p.Gly255Arg)

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.763G>C (p.Gly255Arg)

HGVS:

NC_000017.11:g.58213077C>G
NG_013032.1:g.11529G>C
NM_001321268.2:c.154G>C
NM_001321269.2:c.763G>C
NM_001330397.2:c.763G>C
NM_017777.4:c.763G>CMANE SELECT
NP_001308197.1:p.Gly52Arg
NP_001308198.1:p.Gly255Arg
NP_001317326.1:p.Gly255Arg
NP_060247.2:p.Gly255Arg
NP_060247.2:p.Gly255Arg
LRG_687t1:c.763G>C
LRG_687:g.11529G>C
LRG_687p1:p.Gly255Arg
NC_000017.10:g.56290438C>G
NM_017777.3:c.763G>C

Protein change:

G255R

Links:

dbSNP: rs201237547

NCBI 1000 Genomes Browser:

rs201237547

Molecular consequence:

NM_001321268.2:c.154G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001321269.2:c.763G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001330397.2:c.763G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_017777.4:c.763G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000824226	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824226

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 11, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824226.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 255 of the MKS1 protein (p.Gly255Arg). This variant is present in population databases (rs201237547, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MKS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 546082). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MKS1 protein function. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

ClinVar

Relating variation to medicine