rs28937879

Positions:

chr16-75479230-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_021615.5(CHST6):c.599T>G(p.Leu200Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,611,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

CHST6
NM_021615.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.15

Variant links:

Genes affected

CHST6 (HGNC:6938): (carbohydrate sulfotransferase 6) The protein encoded by this gene is an enzyme that catalyzes the transfer of a sulfate group to the GlcNAc residues of keratan. Keratan sulfate helps maintain corneal transparency. Defects in this gene are a cause of macular corneal dystrophy (MCD). [provided by RefSeq, Jan 2010]

CHST6 links:

ENSG00000203472 (HGNC:):

ENSG00000203472 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 16-75479230-A-C is Pathogenic according to our data. Variant chr16-75479230-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 5075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHST6	NM_021615.5 linkuse as main transcript	c.599T>G	p.Leu200Arg	missense_variant	3/3	ENST00000332272.9	NP_067628.1	Q9GZX3
CHST6	NR_163480.1 linkuse as main transcript	n.733+2587T>G		intron_variant
CHST6	NR_163481.1 linkuse as main transcript	n.577+2587T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHST6	ENST00000332272.9 linkuse as main transcript	c.599T>G	p.Leu200Arg	missense_variant	3/3	3	NM_021615.5	ENSP00000328983.4		Q9GZX3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000225

AC:

AN:

244732

Hom.:

AF XY:

0.000225

AC XY:

AN XY:

133274

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000495

Gnomad NFE exome

AF:

0.000455

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000316

AC:

461

AN:

1459028

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

228

AN XY:

725996

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000587

Gnomad4 NFE exome

AF:

0.000399

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000248

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macular corneal dystrophy

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2024	Variant summary: CHST6 c.599T>G (p.Leu200Arg) results in a non-conservative amino acid change located in the Sulfotransferase domain (IPR000863) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 244732 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHST6 causing Macular Corneal Dystrophy (0.00022 vs 0.0013), allowing no conclusion about variant significance. c.599T>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Macular Corneal Dystrophy (example, El Ashry_2002, Safari_2020, Souzeau_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11818380, 32472422, 35985662). ClinVar contains an entry for this variant (Variation ID: 5075). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 28, 2016	The p.Leu200Arg variant in CHST6 has been reported in at least 17 individuals wi th macular corneal dystrophy who also tested positive for a reduction in keratin sulfate consistent with CHST6 deficiency (14 compound heterozygotes, 1 homozygo te and 2 heterozygotes) (El-Ashry 2002, El-Ashry 2005, Abbruzzese 2004, Klintwor th 2006, Liskova 2008). This variant has been identified in 0.03% (30/115,942) o f chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs28937879). Although it has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . In summary, this variant meets our criteria to be classified as pathogenic for macular corneal dystrophy in an autosomal recessive manner based upon its biall elic occurrence in affected individuals and functional evidence. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 16, 2021	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 200 of the CHST6 protein (p.Leu200Arg). This variant is present in population databases (rs28937879, gnomAD 0.05%). This missense change has been observed in individuals with macular corneal dystrophy (PMID: 11818380, 16568029, 32472422). It has also been observed to segregate with disease in related individuals. This variant is also known as 1291T>G. ClinVar contains an entry for this variant (Variation ID: 5075). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 09, 2019	The CHST6 c.599T>G (p.Leu200Arg) missense variant has been reported in at least seven studies in which it is identified in a total of 37 individuals with macular corneal dystrophy (MCD) type I or II from 31 families, including in seven in a homozygous state (two of whom are related); 19 in a compound heterozygous state (two of whom are related); and 11 in a heterozygous state (two of whom are related) (El-Ashry et al. 2002; Aldave et al. 2004; Klintworth et al. 2006; Gruenauer-Kloevekorn et al. 2008; Liskova et al. 2008; Dudakova et al. 2014; Nowinska et al. 2014). The p.Leu200Arg variant was detected in a heterozygous state in one of 694 control chromosomes and is reported at a frequency of 0.000471 in the European (non-Finnish) population of the Genome Aggregation Database. The Leu200 residue is noted to be highly conserved. Based on the collective evidence, the p.Leu200Arg variant is classified as pathogenic for macular corneal dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 09, 2022	- -

Macular corneal dystrophy, type II

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2019

- -

CHST6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

The CHST6 c.599T>G variant is predicted to result in the amino acid substitution p.Leu200Arg. This variant has been reported along with one or more other CHST6 variants in multiple individuals with macular corneal dystrophy (El-Ashry et al. 2002. PubMed ID: 11818380; Klintworth et al. 2006. PubMed ID: 16568029; Weiss et al. 2008. PubMed ID: 19337156; Safari et al. 2020. PubMed ID: 32472422), and is considered a mutation hot-spot (Aldave et al. 2004. PubMed ID: 15013869). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

.;.;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.4

M;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.8

D;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

D;D;D

Vest4

0.94

MVP

0.91

MPC

1.3

ClinPred

0.64

GERP RS

4.7

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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