chr16-88826822-C-T

Variant names:

• chr16-88826822-C-T
• rs267606838
• NM_000512.5:c.1019G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000512.5(GALNS):​c.1019G>A​(p.Gly340Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,433,274 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G340C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.54
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 4A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr16-88826823-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 2862710.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 16-88826822-C-T is Pathogenic according to our data. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88826822-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 18403.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
GALNS	NM_000512.5	c.1019G>A	p.Gly340Asp	missense_variant	Exon 10 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.1019G>A	p.Gly340Asp	missense_variant	Exon 10 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1433274 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710720

African (AFR) AF: 0.00 AC: 0 AN: 32824

American (AMR) AF: 0.00 AC: 0 AN: 40418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25568

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38108

South Asian (SAS) AF: 0.00 AC: 0 AN: 82730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098580

Other (OTH) AF: 0.0000169 AC: 1 AN: 59276

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:6

Feb 01, 2021

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong);the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein (p.Gly340Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15235041, 20574428, 30458289, 30980944). ClinVar contains an entry for this variant (Variation ID: 18403). 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%. For these reasons, this variant has been classified as Pathogenic. -

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1019G>A (p.Gly340Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1019G>A (p.Gly340Asp) variant is classified as Likely Pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Morquio syndrome Pathogenic:1

Feb 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 192834 control chromosomes. c.1019G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Tomatsu_2004, Wang_2010, Cozma_2015), and some are reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports quantification of GALNS enzymatic product using blood samples from MPS IVA affected patients and normal controls, finding that samples from patients homozygous with the variant showed a nearly complete loss of activity (Cozma_2015). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Jan 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 25287660, 30458289, 34426522, 32860008, 32014045, 24035930, 34387910, 15235041, 22940367, 25501214, 29966168, 29869463, Liang2023[case report], Sung[case report], 26147980, 20574428, 36077388, 30980944, 34573925, 35212421, 35782601, 36000290) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.053	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.86		Gain of catalytic residue at G340 (P = 0.0258);
MVP		0.99
MPC		0.48
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.97
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606838; hg19: chr16-88893230;