VCV000846705.12 - ClinVar

NM_001365999.1(SZT2):c.5285G>A (p.Arg1762His)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001365999.1(SZT2):c.5285G>A (p.Arg1762His)

Variation ID: 846705 Accession: VCV000846705.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 43432282 (GRCh38) [ NCBI UCSC ] 1: 43897953 (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	Apr 15, 2020	Oct 8, 2024	May 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001365999.1:c.5285G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001352928.1:p.Arg1762His	missense
NM_015284.4:c.5114G>A	NP_056099.3:p.Arg1705His	missense
NC_000001.11:g.43432282G>A
NC_000001.10:g.43897953G>A
NG_029091.1:g.47398G>A

... more HGVS ... less HGVS

Protein change

R1705H, R1762H

Other names

Canonical SPDI

NC_000001.11:43432281: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.

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00009

Links

dbSNP: rs779573906 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.
SZT2		-	-	GRCh38 GRCh37	2951	3191

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.
Developmental and epileptic encephalopathy, 18	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV003141979.4
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	May 9, 2024	RCV004678915.1
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 9, 2024	RCV001050073.10

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 (Jul 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 18 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818893.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 18 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004181041.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (May 09, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005165527.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: The c.5114G>A (p.R1705H) alteration is located in exon 36 (coding exon 36) of the SZT2 gene. This alteration results from a G to A substitution … (more) The c.5114G>A (p.R1705H) alteration is located in exon 36 (coding exon 36) of the SZT2 gene. This alteration results from a G to A substitution at nucleotide position 5114, causing the arginine (R) at amino acid position 1705 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 16, 2022)	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: SCV001214161.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1705 of the SZT2 protein (p.Arg1705His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1705 of the SZT2 protein (p.Arg1705His). This variant is present in population databases (rs779573906, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 846705). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. (less)
Uncertain significance (May 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001994422.3 First in ClinVar: Nov 05, 2021 Last updated: Oct 08, 2024	Comment: In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

The c.5114G>A (p.R1705H) alteration is located in exon 36 (coding exon 36) of the SZT2 gene. This alteration results from a G to A substitution at nucleotide position 5114, causing the arginine (R) at amino acid position 1705 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1705 of the SZT2 protein (p.Arg1705His). This variant is present in population databases (rs779573906, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 846705). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.

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 rs779573906 ...

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_001365999.1(SZT2):c.5285G>A (p.Arg1762His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779573906 ...