VCV000598985.6 - ClinVar

NM_002076.4(GNS):c.1594C>G (p.Pro532Ala)

Germline

Classification

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.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002076.4(GNS):c.1594C>G (p.Pro532Ala)

Variation ID: 598985 Accession: VCV000598985.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q14.3 12: 64716806 (GRCh38) [ NCBI UCSC ] 12: 65110586 (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	Dec 16, 2018	Oct 8, 2024	Sep 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002076.4:c.1594C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002067.1:p.Pro532Ala	missense
NC_000012.12:g.64716806G>C
NC_000012.11:g.65110586G>C
NG_008955.1:g.47641C>G

Protein change

P532A

Other names

Canonical SPDI

NC_000012.12:64716805:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.00020 (C)

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

The Genome Aggregation Database (gnomAD) 0.00005

Exome Aggregation Consortium (ExAC) 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00011

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

dbSNP: rs202228620 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.
GNS		-	-	GRCh38 GRCh37	745	759

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-III-D	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 20, 2024	RCV002493366.5
2-3 toe syndactyly Abnormal aggressive, impulsive or violent behavior Aggressive behavior Autism Bulbous nose Clinodactyly of the 5th toe Coarse facial features Cognitive impairment Frontal bossing Global developmental delay Hallux valgus Intellectual disability Intellectual disability, profound Macroglossia Mandibular prognathia Profound global developmental delay Seizure Short toe Shortening of all phalanges of fingers Slit-like opening of the exterior auditory meatus Thick lower lip vermilion Widely spaced teeth	Uncertain significance (1)	criteria provided, single submitter	-	RCV000735356.3

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.	More information 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.
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	2-3 toe syndactyly Abnormal aggressive, impulsive or violent behavior Aggressive behavior Autism Bulbous nose Clinodactyly of the 5th toe Coarse facial features Cognitive impairment Frontal bossing Global developmental delay Hallux valgus Intellectual disability Intellectual disability, profound Macroglossia Mandibular prognathia Profound global developmental delay Seizure Short toe Shortening of all phalanges of fingers Slit-like opening of the exterior auditory meatus Thick lower lip vermilion Widely spaced teeth Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854510.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: male
Uncertain significance (Apr 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-III-D Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002799728.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis, MPS-III-D Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003274812.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 532 of the GNS protein (p.Pro532Ala). … (more) This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 532 of the GNS protein (p.Pro532Ala). This variant is present in population databases (rs202228620, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with GNS-related conditions. ClinVar contains an entry for this variant (Variation ID: 598985). 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 tolerated. 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. (less)
Likely benign (Sep 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-III-D Affected status: no Allele origin: germline	3billion Accession: SCV005328957.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous … (more) The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. (less)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 532 of the GNS protein (p.Pro532Ala). This variant is present in population databases (rs202228620, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with GNS-related conditions. ClinVar contains an entry for this variant (Variation ID: 598985). 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 tolerated. 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs202228620 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_002076.4(GNS):c.1594C>G (p.Pro532Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202228620 ...