VCV001683700.6 - ClinVar

NM_170784.3(MKKS):c.429_434delinsTT (p.Phe144fs)

Germline

Classification

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.

(4)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170784.3(MKKS):c.429_434delinsTT (p.Phe144fs)

Variation ID: 1683700 Accession: VCV001683700.6

Type and length

Indel, 6 bp

Location

Cytogenetic: 20p12.2 20: 10413081-10413086 (GRCh38) [ NCBI UCSC ] 20: 10393729-10393734 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	May 21, 2022	Oct 8, 2024	Apr 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_170784.3:c.429_434delinsTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_740754.1:p.Phe144fs	frameshift
NM_018848.3:c.429_434delinsTT	NP_061336.1:p.Phe144fs	frameshift
NC_000020.11:g.10413081_10413086delinsAA
NC_000020.10:g.10393729_10393734delinsAA
NG_009109.2:g.26133_26138delinsTT
NG_009109.3:g.26136_26141delinsTT

... more HGVS ... less HGVS

Protein change

F144fs

Other names

Canonical SPDI

NC_000020.11:10413080:CTAAAG:AA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 604896.0009 dbSNP: rs2122235362 VarSome

Comment on variant

NCBI staff provided an HGVS expression for allelic variant 604896.0009 from the sequence reported in Figure 2b of the paper by Katsanis et al., 2000 (PubMed 10973251).

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
MKKS		-	-	GRCh38 GRCh37	582	638

Conditions - Germline

Condition Help 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.
Bardet-Biedl syndrome 6 McKusick-Kaufman syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 15, 2022	RCV002502052.1
Bardet-Biedl syndrome 6	Likely pathogenic (2)	criteria provided, single submitter	Aug 17, 2021	RCV002244221.4
McKusick-Kaufman syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003221313.2

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.
Likely pathogenic (Aug 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 6 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512604.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PVS1 very strong, PM2 moderate Geographic origin: Brazil
Pathogenic (Feb 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	McKusick-Kaufman syndrome Bardet-Biedl syndrome 6 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812743.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	McKusick-Kaufman syndrome Affected status: yes Allele origin: paternal	Daryl Scott Lab, Baylor College of Medicine Accession: SCV003915719.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 37673932
Pathogenic (Sep 01, 2000)	no assertion criteria provided Method: literature only	BARDET-BIEDL SYNDROME 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025822.5 First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2024	Publications: PubMed (2) PubMed: 10973251‚ 10973238 Comment on evidence: In 2 affected members of a Newfoundland family segregating Bardet-Biedl syndrome-6 (BBS6; 605231), Katsanis et al. (2000) detected homozygosity for a complex 429delCT/433delAG allele of … (more) In 2 affected members of a Newfoundland family segregating Bardet-Biedl syndrome-6 (BBS6; 605231), Katsanis et al. (2000) detected homozygosity for a complex 429delCT/433delAG allele of the MKKS gene that resulted in a frameshift of the termination of the protein at amino acid 157. Cloning and sequencing of the PCR product from 1 subject indicated that both deletions were on the same strand, suggesting that this mutation arose through a complex mechanism. In an independent study of the same Newfoundland family (their family 2) segregating BBS6, Slavotinek et al. (2000) identified homozygosity for 2 deletions in the MKKS gene, which they designated 1316delC and 1324-1326delGTA, in exon 3 of the MKKS gene, predicting a frameshift. In an erratum, Slavotinek et al. (2000) attributed the discrepancy in the naming of this mutation to ambiguity in the nomenclature system and the absence of biologic data that could resolve the discrepancy. The parents in this family were related. The proband and her affected brother had retinitis pigmentosa, postaxial polydactyly, mild mental retardation, morbid obesity, lobulated kidneys with prominent calyces, and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister had similar phenotypic features (retinitis pigmentosa with blindness by age 13, BMI greater than 45, abnormal glucose tolerance test, an IQ of 64, vaginal atresia, and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Katsanis et al. (2000) identified 2 affected members of another Newfoundland family with BBS6 who were compound heterozygous for this complex mutation and another frameshift mutation (604896.0007). (less)

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

Title	Author	Journal	Year	Link
Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return.	Huth EA	European journal of human genetics : EJHG	2023	PMID: 37673932
Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.	Katsanis N	Nature genetics	2000	PMID: 10973251
Mutations in MKKS cause Bardet-Biedl syndrome.	Slavotinek AM	Nature genetics	2000	PMID: 10973238

Text-mined citations for rs2122235362 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_170784.3(MKKS):c.429_434delinsTT (p.Phe144fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2122235362 ...