VCV000008599.13 - ClinVar

NM_175875.5(SIX5):c.886G>A (p.Ala296Thr)

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.

(9)

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); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_175875.5(SIX5):c.886G>A (p.Ala296Thr)

Variation ID: 8599 Accession: VCV000008599.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 45767073 (GRCh38) [ NCBI UCSC ] 19: 46270331 (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 4, 2013	Oct 8, 2024	Oct 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_175875.5:c.886G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_787071.3:p.Ala296Thr	missense
NC_000019.10:g.45767073C>T
NC_000019.9:g.46270331C>T
NG_012745.1:g.7167G>A
NG_046372.1:g.381C>T
	Q8N196:p.Ala296Thr

... more HGVS ... less HGVS

Protein change

A296T

Other names

Canonical SPDI

NC_000019.10:45767072:C: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.

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

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00005

The Genome Aggregation Database (gnomAD) 0.00009

Trans-Omics for Precision Medicine (TOPMed) 0.00015

Links

ClinGen: CA340797 UniProtKB: Q8N196#VAR_032942 OMIM: 600963.0002 dbSNP: rs80356462 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.
LOC107075317	-	-	-	GRCh38	-	414
SIX5		-	-	GRCh38 GRCh37	178	369

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.
Branchiootorenal syndrome 2	Uncertain significance (3)	criteria provided, single submitter	Jan 19, 2021	RCV000009130.10
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Oct 16, 2023	RCV001723554.7
SIX5-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 11, 2024	RCV004752693.1

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.
Uncertain significance (Jan 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Branchiootorenal syndrome 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003823287.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Oct 16, 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: SCV004266979.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 17357085 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 296 of the SIX5 protein (p.Ala296Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 296 of the SIX5 protein (p.Ala296Thr). This variant is present in population databases (rs80356462, gnomAD 0.02%). This missense change has been observed in individual(s) with Branchio-Oto-Renal Syndrome (PMID: 17357085). ClinVar contains an entry for this variant (Variation ID: 8599). 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 SIX5 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SIX5 function (PMID: 17357085). 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 (Feb 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002005566.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 17357085, 31589614)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005209694.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Pathogenic (Apr 01, 2007)	no assertion criteria provided Method: literature only	BRANCHIOOTORENAL SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029347.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2014	Publications: PubMed (1) PubMed: 17357085 Comment on evidence: In a patient with a clinical diagnosis of branchiootorenal syndrome (BOR2; 610896) who had bilateral dysplastic kidneys and reduced renal function, bilateral hearing loss and … (more) In a patient with a clinical diagnosis of branchiootorenal syndrome (BOR2; 610896) who had bilateral dysplastic kidneys and reduced renal function, bilateral hearing loss and cervical fistulae, and right-sided hemifacial microsomia, preauricular sinus, and pinna malformation, Hoskins et al. (2007) identified a heterozygous 886G-A transition in the SIX5 gene that resulted in an ala296-to-thr (A296T) amino acid substitution. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957588.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001965525.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Uncertain significance (Mar 11, 2024)	no assertion criteria provided Method: clinical testing	SIX5-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005351904.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SIX5 c.886G>A variant is predicted to result in the amino acid substitution p.Ala296Thr. This variant has been reported in the heterozygous state in an … (more) The SIX5 c.886G>A variant is predicted to result in the amino acid substitution p.Ala296Thr. This variant has been reported in the heterozygous state in an individual with branchio-oto-renal syndrome (Hoskins et al. 2007. PubMed ID: 17357085). Experimental studies using a yeast two-hybrid assay and a luciferase assay were inconclusive (Hoskins et al. 2007. PubMed ID: 17357085). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD, including more than 280 heterozygotes in the gnomAD v4.0.0 dataset. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
not provided (-)	no classification provided Method: literature only	Branchiootorenal syndrome 2 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000041680.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 17357085 Bookshelf: NBK1380 Bookshelf: NBK1380

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 296 of the SIX5 protein (p.Ala296Thr). This variant is present in population databases (rs80356462, gnomAD 0.02%). This missense change has been observed in individual(s) with Branchio-Oto-Renal Syndrome (PMID: 17357085). ClinVar contains an entry for this variant (Variation ID: 8599). 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 SIX5 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SIX5 function (PMID: 17357085). 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 SIX5 c.886G>A variant is predicted to result in the amino acid substitution p.Ala296Thr. This variant has been reported in the heterozygous state in an individual with branchio-oto-renal syndrome (Hoskins et al. 2007. PubMed ID: 17357085). Experimental studies using a yeast two-hybrid assay and a luciferase assay were inconclusive (Hoskins et al. 2007. PubMed ID: 17357085). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD, including more than 280 heterozygotes in the gnomAD v4.0.0 dataset. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Branchiootorenal Spectrum Disorder.	Adam MP	-	2018	PMID: 20301554
Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.	Hoskins BE	American journal of human genetics	2007	PMID: 17357085

Text-mined citations for rs80356462 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_175875.5(SIX5):c.886G>A (p.Ala296Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80356462 ...