VCV000007792.8 - ClinVar

NM_004482.4(GALNT3):c.484C>T (p.Arg162Ter)

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.

(5)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004482.4(GALNT3):c.484C>T (p.Arg162Ter)

Variation ID: 7792 Accession: VCV000007792.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 165770217 (GRCh38) [ NCBI UCSC ] 2: 166626727 (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	May 26, 2018	Feb 20, 2024	Jan 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004482.4:c.484C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004473.2:p.Arg162Ter	nonsense
NC_000002.12:g.165770217G>A
NC_000002.11:g.166626727G>A
NG_012069.1:g.29077C>T

Protein change

R162*

Other names

Canonical SPDI

NC_000002.12:165770216:G:A

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 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00007

Exome Aggregation Consortium (ExAC) 0.00012

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00020

The Genome Aggregation Database (gnomAD) 0.00021

Links

ClinGen: CA119079 OMIM: 601756.0002 dbSNP: rs137853086 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.
GALNT3		-	-	GRCh38 GRCh37	433	496

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.
Tumoral calcinosis, hyperphosphatemic, familial, 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 27, 2023	RCV000008235.6
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 9, 2024	RCV000807812.7

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.
Pathogenic (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Tumoral calcinosis, hyperphosphatemic, familial, 1 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000883276.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (2) PubMed: 15133511‚ 15687324 Comment: This variant is interpreted as Pathogenic, for Tumoral calcinosis, hyperphosphatemic, familial, 1, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls … (more) This variant is interpreted as Pathogenic, for Tumoral calcinosis, hyperphosphatemic, familial, 1, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1-Moderate => PP1 upgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/15133511). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/15687324) (https://www.ncbi.nlm.nih.gov/pubmed/15133511). (less)
Pathogenic (Jan 18, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002549578.2 First in ClinVar: Jul 23, 2022 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24668887, 25351881, 31589614, 26337219, 20358599, 15687324, 15133511) (less)
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tumoral calcinosis, hyperphosphatemic, familial, 1 Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004013154.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PVS1, PM2, PM3 Secondary finding: yes
Pathogenic (Jan 09, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000947886.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 15133511‚ 20358599‚ 24668887‚ 25351881‚ 26337219 Comment: This sequence change creates a premature translational stop signal (p.Arg162) in the GALNT3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg162) in the GALNT3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALNT3 are known to be pathogenic (PMID: 15133511, 20358599). This variant is present in population databases (rs137853086, gnomAD 0.09%). This premature translational stop signal has been observed in individuals with tumoral calcinosis (PMID: 15133511, 24668887, 25351881, 26337219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7792). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2005)	no assertion criteria provided Method: literature only	TUMORAL CALCINOSIS, HYPERPHOSPHATEMIC, FAMILIAL, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028442.3 First in ClinVar: Apr 04, 2013 Last updated: May 26, 2018	Publications: PubMed (3) PubMed: 8338191‚ 15133511‚ 15687324 Comment on evidence: In affected members of an African American family with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900) studied by Slavin et al. (1993), Topaz et al. (2004) … (more) In affected members of an African American family with hyperphosphatemic familial tumoral calcinosis (HFTC1; 211900) studied by Slavin et al. (1993), Topaz et al. (2004) found compound heterozygosity for 2 mutations in the GALNT3 gene: a nonsense mutation 484C-T, resulting in the amino acid substitution arg162-to-stop (R162X) in exon 1; and a splice site mutation, IVS7+5G-A (601756.0003). See also 601756.0004 and Ichikawa et al. (2005). (less)

Comment:

This variant is interpreted as Pathogenic, for Tumoral calcinosis, hyperphosphatemic, familial, 1, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1-Moderate => PP1 upgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/15133511). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/15687324) (https://www.ncbi.nlm.nih.gov/pubmed/15133511).

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24668887, 25351881, 31589614, 26337219, 20358599, 15687324, 15133511)

Comment:

This sequence change creates a premature translational stop signal (p.Arg162*) in the GALNT3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALNT3 are known to be pathogenic (PMID: 15133511, 20358599). This variant is present in population databases (rs137853086, gnomAD 0.09%). This premature translational stop signal has been observed in individuals with tumoral calcinosis (PMID: 15133511, 24668887, 25351881, 26337219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7792). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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

Title	Author	Journal	Year	Link
Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).	Vieira AR	Oral surgery, oral medicine, oral pathology and oral radiology	2015	PMID: 26337219
GALNT3 gene mutation-associated chronic recurrent multifocal osteomyelitis and familial hyperphosphatemic familial tumoral calcinosis.	Demellawy DE	Scandinavian journal of rheumatology	2015	PMID: 25351881
Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms.	Finer G	American journal of medical genetics. Part A	2014	PMID: 24668887
Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.	Ichikawa S	American journal of medical genetics. Part A	2010	PMID: 20358599
A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive.	Ichikawa S	The Journal of clinical endocrinology and metabolism	2005	PMID: 15687324
Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.	Topaz O	Nature genetics	2004	PMID: 15133511
Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis.	Slavin RE	The American journal of surgical pathology	1993	PMID: 8338191

Text-mined citations for rs137853086 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004482.4(GALNT3):c.484C>T (p.Arg162Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137853086 ...