VCV000339054.8 - ClinVar

NM_001001433.3(STX16):c.644A>T (p.His215Leu)

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.

(3)

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(2); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001001433.3(STX16):c.644A>T (p.His215Leu)

Variation ID: 339054 Accession: VCV000339054.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.32 20: 58670599 (GRCh38) [ NCBI UCSC ] 20: 57245655 (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 6, 2016	May 1, 2024	Nov 7, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001001433.3:c.644A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001001433.1:p.His215Leu	missense
NM_001134772.3:c.632A>T	NP_001128244.1:p.His211Leu	missense
NM_001134773.3:c.593A>T	NP_001128245.1:p.His198Leu	missense
NM_001204868.2:c.485A>T	NP_001191797.1:p.His162Leu	missense
NM_003763.6:c.581A>T	NP_003754.2:p.His194Leu	missense
NR_037941.2:n.1154A>T		non-coding transcript variant
NR_037942.2:n.547A>T		non-coding transcript variant
NR_037943.2:n.504A>T		non-coding transcript variant
NR_037945.1:n.1398A>T		non-coding transcript variant
NC_000020.11:g.58670599A>T
NC_000020.10:g.57245655A>T
NG_011831.2:g.24328A>T

... more HGVS ... less HGVS

Protein change

H215L, H198L, H162L, H194L, H211L

Other names

Canonical SPDI

NC_000020.11:58670598:A:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00009

Exome Aggregation Consortium (ExAC) 0.00010

1000 Genomes Project 30x 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00016

The Genome Aggregation Database (gnomAD) 0.00017

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

ClinGen: CA9925381 dbSNP: rs185111037 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.
STX16		-	-	GRCh38 GRCh37	4	230
STX16-NPEPL1	-	-	-	GRCh38	-	258

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.
Pseudohypoparathyroidism type 1B	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000398773.5
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Dec 6, 2022	RCV002520025.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 7, 2023	RCV002520026.3

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.
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Pseudohypoparathyroidism type 1B Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000434787.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Uncertain significance (Nov 07, 2023)	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: SCV003248338.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Comment: This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 215 of the STX16 protein (p.His215Leu). … (more) This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 215 of the STX16 protein (p.His215Leu). This variant is present in population databases (rs185111037, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STX16-related conditions. ClinVar contains an entry for this variant (Variation ID: 339054). 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 not expected to disrupt STX16 protein function with a negative predictive value of 80%. 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 (Dec 06, 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: SCV003711911.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.644A>T (p.H215L) alteration is located in exon 6 (coding exon 6) of the STX16 gene. This alteration results from a A to T substitution … (more) The c.644A>T (p.H215L) alteration is located in exon 6 (coding exon 6) of the STX16 gene. This alteration results from a A to T substitution at nucleotide position 644, causing the histidine (H) at amino acid position 215 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 215 of the STX16 protein (p.His215Leu). This variant is present in population databases (rs185111037, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STX16-related conditions. ClinVar contains an entry for this variant (Variation ID: 339054). 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 not expected to disrupt STX16 protein function with a negative predictive value of 80%. 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 c.644A>T (p.H215L) alteration is located in exon 6 (coding exon 6) of the STX16 gene. This alteration results from a A to T substitution at nucleotide position 644, causing the histidine (H) at amino acid position 215 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, 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

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 rs185111037 ...

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_001001433.3(STX16):c.644A>T (p.His215Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs185111037 ...