NM_170784.3(MKKS):c.830T>C (p.Leu277Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 21, 2024
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:: RCV001851675.4

Allele description [Variation Report for NM_170784.3(MKKS):c.830T>C (p.Leu277Pro)]

NM_170784.3(MKKS):c.830T>C (p.Leu277Pro)

Gene:

MKKS:MKKS centrosomal shuttling protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20p12.2

Genomic location:

Preferred name:

NM_170784.3(MKKS):c.830T>C (p.Leu277Pro)

HGVS:

NC_000020.11:g.10412685A>G
NG_009109.2:g.26534T>C
NM_018848.3:c.830T>C
NM_170784.3:c.830T>CMANE SELECT
NP_061336.1:p.Leu277Pro
NP_740754.1:p.Leu277Pro
NC_000020.10:g.10393333A>G
NM_018848.2:c.830T>C
NM_170784.3:c.830T>C
Q9NPJ1:p.Leu277Pro

Protein change:

L277P; LEU277PRO

Links:

UniProtKB: Q9NPJ1#VAR_009884; OMIM: 604896.0008; dbSNP: rs74315398

NCBI 1000 Genomes Browser:

rs74315398

Molecular consequence:

NM_018848.3:c.830T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170784.3:c.830T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Bardet-Biedl syndrome (BBS)
Identifiers:: MONDO: MONDO:0015229; MedGen: C0752166; Orphanet: 110; OMIM: PS209900

Name:: McKusick-Kaufman syndrome (MKKS)
Synonyms:: Hydrometrocolpos syndrome; Hydrometrocolpos, postaxial polydactyly, and congenital heart malformation
Identifiers:: MONDO: MONDO:0009367; MedGen: C0948368; Orphanet: 2473; OMIM: 236700

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002236624	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10973251, 20498079, 22446187, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002236624

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 21, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.

Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ, Davidson WS, Lupski JR.

Nat Genet. 2000 Sep;26(1):67-70.

PubMed [citation]

PMID:: 10973251

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.

Zaghloul NA, Liu Y, Gerdes JM, Gascue C, Oh EC, Leitch CC, Bromberg Y, Binkley J, Leibel RL, Sidow A, Badano JL, Katsanis N.

Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10602-7. doi: 10.1073/pnas.1000219107. Epub 2010 May 24.

PubMed [citation]

PMID:: 20498079
PMCID:: PMC2890780

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002236624.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 277 of the MKKS protein (p.Leu277Pro). This variant is present in population databases (rs74315398, gnomAD 0.009%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 10973251). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5314). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MKKS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MKKS function (PMID: 20498079, 22446187). For these reasons, this variant has been classified as Pathogenic.

#	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: Nov 10, 2024

ClinVar

Relating variation to medicine