rs386834044

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_017777.4(MKS1):c.1450_1453dupGGCA(p.Thr485ArgfsTer107) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000266 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T485T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MKS1
NM_017777.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.39

Variant links:

Genes affected

MKS1 (HGNC:7121): (MKS transition zone complex subunit 1) The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MKS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-58206501-G-GTGCC is Pathogenic according to our data. Variant chr17-58206501-G-GTGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4 link	c.1450_1453dupGGCA	p.Thr485ArgfsTer107	frameshift_variant	Exon 16 of 18	ENST00000393119.7	NP_060247.2	Q9NXB0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7 link	c.1450_1453dupGGCA	p.Thr485ArgfsTer107	frameshift_variant	Exon 16 of 18	1	NM_017777.4	ENSP00000376827.2		Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000722

AC:

AN:

249270

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.000475

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53286

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1112008

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000207211

AN:

0.000207211

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 1

Pathogenic:3

Dec 05, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bardet-Biedl syndrome 13

Pathogenic:3

Mar 01, 2023

Pediatrics Genetics, Post Graduate Institute of Medical Education and Research

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PP5 -

Dec 05, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 24, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome

Pathogenic:1

Feb 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change inserts 4 nucleotides in exon 16 of the MKS1 mRNA (c.1450_1453dupGGCA), causing a frameshift at codon 485. This creates a premature translational stop signal (p.Thr485Argfs*107) and is expected to result in an absent or disrupted protein product. Truncating variants in MKS1 are known to be pathogenic. This particular truncation has been reported in the homozygous state from an individual affected with Meckel Gruber syndrome in the literature (PMID: 17397051, 17185389). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108 in the literature. For these reasons, this variant has been classified as Pathogenic. -

Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28

Pathogenic:1

Mar 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 28

Pathogenic:1

Dec 05, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

May 02, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MKS1-related disorder

Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MKS1 c.1450_1453dupGGCA (p.Thr485ArgfsTer107) variant, also known as c.1448_1451dupCAGG, results in a frameshift and is predicted to cause an elongation of the protein. Across a selection of available literature, the p.Thr485ArgfsTer107 variant was identified in a homozygous state in four individuals with Meckel syndrome from consanguineous families of Pakistani origin (Dawe et al. 2007; Khaddour et al. 2007; Szymanska et al. 2012). The p.Thr485ArgfsTer107 variant has not been reported in any cases of Bardet-Biedl syndrome. The variant was absent from 96 healthy controls but is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. Dawe et al. (2007) conducted immunohistochemistry staining in kidney tissue from an affected individual carrying the p.Thr485ArgfsTer107 variant and demonstrated a lack of MKS1 protein compared to age-matched control tissue. Based on the evidence from the literature and potential impact of frameshift variants, the p.Thr485ArgfsTer107 variant is classified as likely pathogenic for MKS1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Pathogenic:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change results in a frameshift in the MKS1 gene (p.Thr485Argfs*107). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the MKS1 protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs386834044, gnomAD 0.06%). This frameshift has been observed in individual(s) with Meckel Gruber syndrome (PMID: 17185389, 17397051). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108. ClinVar contains an entry for this variant (Variation ID: 56617). This variant results in an extension of the MKS1 protein. Other variant(s) that result in a similarly extended protein product (p.Arg510Profs*81) have been observed in individuals with MKS1-related disease (PMID: 26490104). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=0/200

disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over