VCV000286884.41 - ClinVar

NM_017777.4(MKS1):c.1388G>A (p.Arg463Gln)

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.

(15)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(4); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017777.4(MKS1):c.1388G>A (p.Arg463Gln)

Variation ID: 286884 Accession: VCV000286884.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58207104 (GRCh38) [ NCBI UCSC ] 17: 56284465 (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	Dec 6, 2016	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_017777.4:c.1388G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060247.2:p.Arg463Gln	missense
NM_001321268.2:c.779G>A	NP_001308197.1:p.Arg260Gln	missense
NM_001321269.2:c.1388G>A	NP_001308198.1:p.Arg463Gln	missense
NM_001330397.2:c.1274-724G>A		intron variant
NC_000017.11:g.58207104C>T
NC_000017.10:g.56284465C>T
NG_013020.1:g.19377C>T
NG_013032.1:g.17502G>A
LRG_687:g.17502G>A
LRG_687t1:c.1388G>A	LRG_687p1:p.Arg463Gln

... more HGVS ... less HGVS

Protein change

R463Q, R260Q

Other names

Canonical SPDI

NC_000017.11:58207103:C:T

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.

0.00060 (T)

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

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00109

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00206

Exome Aggregation Consortium (ExAC) 0.00212

The Genome Aggregation Database (gnomAD), exomes 0.00220

The Genome Aggregation Database (gnomAD) 0.00235

Trans-Omics for Precision Medicine (TOPMed) 0.00264

Links

ClinGen: CA8669152 dbSNP: rs201619500 VarSome

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.
MKS1		-	-	GRCh38 GRCh37	980	1067

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.
Meckel syndrome, type 1	Uncertain significance (2)	criteria provided, single submitter	Jan 13, 2018	RCV000285730.7
Bardet-Biedl syndrome	Likely pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV000400230.4
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Dec 14, 2023	RCV000335464.12
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000514906.21
Bardet-Biedl syndrome 13	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001094550.5
Familial aplasia of the vermis Meckel-Gruber syndrome	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001083793.9

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 benign (Mar 14, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340469.4 First in ClinVar: Dec 06, 2016 Last updated: Apr 09, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MKS1 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Meckel syndrome, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000404277.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Bardet-Biedl syndrome 13 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000404279.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Benign (Sep 22, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595792.2 First in ClinVar: Dec 06, 2016 Last updated: Jun 13, 2020
Likely benign (Jul 01, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565134.4 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 27353947, 31456290)
Benign (Dec 14, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241496.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: Variant summary: MKS1 c.1388G>A (p.Arg463Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: MKS1 c.1388G>A (p.Arg463Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249540 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1388G>A in individuals affected with Meckel Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic n=1, VUS n=1, likely benign/benign n=7). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial aplasia of the vermis Meckel-Gruber syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000758411.7 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024
Likely benign (Mar 09, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610174.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004145719.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: MKS1: BP4, BS1, BS2 Number of individuals with the variant: 9
Likely pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Bardet-Biedl syndrome Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161136.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020
Benign (Jan 07, 2020)	no assertion criteria provided Method: clinical testing	Meckel syndrome type 1 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453199.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799640.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920659.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927800.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001966007.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Variant summary: MKS1 c.1388G>A (p.Arg463Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249540 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1388G>A in individuals affected with Meckel Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic n=1, VUS n=1, likely benign/benign n=7). Based on the evidence outlined above, the variant was classified as benign.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MKS1	-	-	-	-

Text-mined citations for rs201619500 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_017777.4(MKS1):c.1388G>A (p.Arg463Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201619500 ...