VCV000873320.8 - ClinVar

NM_033409.4(SLC52A3):c.802C>T (p.Arg268Trp)

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
Likely pathogenic(2); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033409.4(SLC52A3):c.802C>T (p.Arg268Trp)

Variation ID: 873320 Accession: VCV000873320.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p13 20: 763769 (GRCh38) [ NCBI UCSC ] 20: 744413 (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 31, 2020	May 1, 2024	Dec 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_033409.4:c.802C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_212134.3:p.Arg268Trp	missense
NM_001370085.1:c.802C>T	NP_001357014.1:p.Arg268Trp	missense
NM_001370086.1:c.802C>T	NP_001357015.1:p.Arg268Trp	missense
NC_000020.11:g.763769G>A
NC_000020.10:g.744413G>A
NG_027687.2:g.17217C>T
LRG_1394:g.17217C>T
LRG_1394t1:c.802C>T	LRG_1394p1:p.Arg268Trp

... more HGVS ... less HGVS

Protein change

R268W

Other names

Canonical SPDI

NC_000020.11:763768: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 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs145498634 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.
SLC52A3		-	-	GRCh38 GRCh37	440	504

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.
Madras motor neuron disease	Likely pathogenic (1)	criteria provided, single submitter	Mar 31, 2020	RCV001095540.1
Brown-Vialetto-van Laere syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Sep 1, 2022	RCV001203115.5
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	May 12, 2022	RCV002411628.2
Auditory neuropathy	Likely pathogenic (1)	criteria provided, single submitter	Dec 22, 2023	RCV003483781.1

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.
Likely pathogenic (Mar 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Madras motor neuron disease Affected status: yes Allele origin: germline	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University Accession: SCV001251042.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Number of individuals with the variant: 1 Geographic origin: Anatolian Peninsula
Uncertain significance (Sep 01, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Brown-Vialetto-van Laere syndrome 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001374262.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the SLC52A3 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the SLC52A3 protein (p.Arg268Trp). This variant is present in population databases (rs145498634, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC52A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 873320). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 pathogenic (Dec 22, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Auditory neuropathy Affected status: yes Allele origin: germline	WangQJ Lab, Chinese People's Liberation Army General Hospital Accession: SCV004229045.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Number of individuals with the variant: 1 Ethnicity/Population group: Asian Geographic origin: China
Uncertain significance (May 12, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002675972.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 32579787 Comment: The p.R268W variant (also known as c.802C>T), located in coding exon 2 of the SLC52A3 gene, results from a C to T substitution at nucleotide … (more) The p.R268W variant (also known as c.802C>T), located in coding exon 2 of the SLC52A3 gene, results from a C to T substitution at nucleotide position 802. The arginine at codon 268 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in the homozygous state in an individual with Madras motor neuron disease; however, clinical details were limited (Tunca C et al. Hum Mutat, 2020 08;41:e7-e45). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the SLC52A3 protein (p.Arg268Trp). This variant is present in population databases (rs145498634, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC52A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 873320). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

The p.R268W variant (also known as c.802C>T), located in coding exon 2 of the SLC52A3 gene, results from a C to T substitution at nucleotide position 802. The arginine at codon 268 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in the homozygous state in an individual with Madras motor neuron disease; however, clinical details were limited (Tunca C et al. Hum Mutat, 2020 08;41:e7-e45). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database.	Tunca C	Human mutation	2020	PMID: 32579787

Text-mined citations for rs145498634 ...

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_033409.4(SLC52A3):c.802C>T (p.Arg268Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145498634 ...