VCV002909463.3 - ClinVar

NM_000512.5(GALNS):c.700G>T (p.Ala234Ser)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely pathogenic

This classification is based on the single submission received

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000512.5(GALNS):c.700G>T (p.Ala234Ser)

Variation ID: 2909463 Accession: VCV002909463.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 88835783 (GRCh38) [ NCBI UCSC ] 16: 88902191 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2024	Feb 23, 2026	Jun 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000512.5:c.700G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000503.1:p.Ala234Ser	missense
NM_001323543.2:c.145G>T	NP_001310472.1:p.Ala49Ser	missense
NM_001323544.2:c.718G>T	NP_001310473.1:p.Ala240Ser	missense
NC_000016.10:g.88835783C>A
NC_000016.9:g.88902191C>A
NG_008667.1:g.26184G>T

... more HGVS ... less HGVS

Protein change

A234S, A240S, A49S

Other names

Canonical SPDI

NC_000016.10:88835782:C:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA8235025 dbSNP: rs368603508 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GALNS		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1206	1513

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mucopolysaccharidosis, MPS-IV-A	Likely pathogenic (1)	criteria provided, single submitter	Jun 27, 2023	RCV003598651.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jun 27, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Mucopolysaccharidosis, MPS-IV-A	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004537987.3 First in ClinVar: Feb 20, 2024 Last updated: Feb 23, 2026	Publications: PubMed (1) PubMed: 34387910 Comment: show In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala234 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34387910; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with GALNS-related conditions. This variant is present in population databases (rs368603508, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 234 of the GALNS protein (p.Ala234Ser). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala234 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34387910; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with GALNS-related conditions. This variant is present in population databases (rs368603508, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 234 of the GALNS protein (p.Ala234Ser).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants.	Zanetti A	Human mutation	2021	PMID: 34387910

Text-mined citations for rs368603508 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 25, 2026