rs118204437

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000512.5(GALNS):c.1156C>T(p.Arg386Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,613,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1O:1

Conservation

PhyloP100: 7.37

Variant links:

Genes affected

GALNS (HGNC:4122): (galactosamine (N-acetyl)-6-sulfatase) This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder. [provided by RefSeq, Jul 2008]

GALNS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000512.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-88824852-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1048232.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 16-88824853-G-A is Pathogenic according to our data. Variant chr16-88824853-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 700.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Pathogenic=9, Uncertain_significance=1}. Variant chr16-88824853-G-A is described in Lovd as [Pathogenic]. Variant chr16-88824853-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5 linkuse as main transcript	c.1156C>T	p.Arg386Cys	missense_variant	11/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10 linkuse as main transcript	c.1156C>T	p.Arg386Cys	missense_variant	11/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000923

AC:

AN:

249270

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1460932

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000991

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Pathogenic:9Uncertain:1Other:1

Pathogenic, criteria provided, single submitter	research	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	De novo (both maternity and paternity confirmed) in a patient with the disease and no family history (PS2_strong); in vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1_supporting); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 01, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 7795586, 8829629, 25287660, 22940367] -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 09, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the GALNS protein (p.Arg386Cys). This variant is present in population databases (rs118204437, gnomAD 0.05%). This missense change has been observed in individuals with Morquio syndrome (PMID: 7795586, 9298823, 22976768, 23227063, 24726177, 26147980). ClinVar contains an entry for this variant (Variation ID: 700). 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 expected to disrupt GALNS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALNS function (PMID: 7795586, 15309681). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital	Feb 23, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed splice region c.3816+4A>G variant in FANCI gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3816+4A>G variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been sumitted to the ClinVar database as Uncertain Significance. However, additional functional stuides will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Morquio syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2017	Variant summary: The GALNS c.1156C>T (p.Arg386Cys) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study, Fukuda_1996, supports these predictions with the observation that the variant causes deficient GALNS activity. This variant was found in 23/275538 control chromosomes (gnomAD) at a frequency of 0.0000835, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALNS variant (0.0020412). Multiple publications have cited the variant in affected homozygous and compound heterozygous pts. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2024	The p.Arg392Cys variant in GALNS has been reported in the homozygous or heterozygous state in >12 individuals (>4 homozygotes, >8 compound heterozygotes) with mucopolysaccharidosis type 4A (MPS 4A). At least 2 of these individuals underwent biochemical analyses that showed markedly reduced GALNS enzyme activity (Ogawa 1995 PMID: 7795586, Bunge 1997 PMID: 9298823, Lee 2012 PMID: 23227063, Pollard 2013 PMID: 22976768, Morrone 2014 PMID: 24726177, Jazela-Stanek 2019 PMID: 30927141, Fang 2022 PMID: 34813777). This variant segregated with disease in at least 2 affected relatives from 2 families (Jazela-Stanek 2019 PMID: 30927141). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 700) and has been identified in 0.03% (4/15280) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that this variant reduces GALNS activity (Ogawa 1995 PMID: 7795586) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive mucopolysaccharidosis type 4A. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting, PP4. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15309681, 23401410, 25287660, 15241807, 10814710, 23876334, 15235041, 25137622, 12442278, 26502894, 7795586, 8829629, 24726177, 16287098, 22940367, 30927141, 34426522, 31589614, 34896230, 33636292, 9375852, 9298823, 34504088) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

0.95

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0020

Sift4G

Benign

0.22

Polyphen

1.0

Vest4

0.92

MutPred

0.92

Loss of methylation at R386 (P = 0.0197);

MVP

0.99

MPC

0.59

ClinPred

0.45

GERP RS

4.7

Varity_R

0.79

gMVP

0.90

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