Submissions for variant NM_000512.5(GALNS):c.1127G>A (p.Arg376Gln)

gnomAD frequency: 0.00173  dbSNP: rs150734270

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173702	SCV000224847	uncertain significance	not provided	2016-04-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697370	SCV000825976	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 376 of the GALNS protein (p.Arg376Gln). This variant is present in population databases (rs150734270, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with mucopolysaccharidosis IVA (PMID: 9521421, 15235041). ClinVar contains an entry for this variant (Variation ID: 193597). 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 not expected to disrupt GALNS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000697370	SCV001274178	likely benign	Mucopolysaccharidosis, MPS-IV-A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000697370	SCV001547898	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	No evidence available
Genome-Nilou Lab	RCV000697370	SCV002044940	likely benign	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000173702	SCV002061578	uncertain significance	not provided	2021-09-27	criteria provided, single submitter	clinical testing	BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844067	SCV002103523	uncertain significance	not specified	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.1127G>A (p.Arg376Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 247092 control chromosomes, predominantly at a frequency of 0.0042 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1127G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A), including at least one homozygote (Yamada_1998, Tomatsu_2004, Chuang_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.