VCV000043540.30 - ClinVar

NM_000441.2(SLC26A4):c.2139T>G (p.Ile713Met)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000441.2(SLC26A4):c.2139T>G (p.Ile713Met)

Variation ID: 43540 Accession: VCV000043540.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q22.3 7: 107710103 (GRCh38) [ NCBI UCSC ] 7: 107350548 (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 9, 2018	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000441.2:c.2139T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000432.1:p.Ile713Met	missense
NC_000007.14:g.107710103T>G
NC_000007.13:g.107350548T>G
NG_008489.1:g.54469T>G

Protein change

I713M

Other names

Canonical SPDI

NC_000007.14:107710102:T:G

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.

0.00200 (G)

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

The Genome Aggregation Database (gnomAD), exomes 0.00068

Exome Aggregation Consortium (ExAC) 0.00078

The Genome Aggregation Database (gnomAD) 0.00268

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00284

Trans-Omics for Precision Medicine (TOPMed) 0.00316

1000 Genomes Project 0.00200

1000 Genomes Project 30x 0.00219

Links

ClinGen: CA132705 dbSNP: rs143708308 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.
LOC123956210	-	-	-	GRCh38	-	75
SLC26A4		-	-	GRCh38 GRCh37	1386	1585

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.
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Mar 13, 2022	RCV000036475.12
Pendred syndrome	Likely benign (2)	criteria provided, single submitter	Dec 28, 2017	RCV000671686.2
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000947056.21
SLC26A4-related disorder	Benign (1)	no assertion criteria provided	Jan 27, 2020	RCV004534765.2

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 (Mar 13, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002500348.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (1) PubMed: 30245029 Comment: Variant summary: SLC26A4 c.2139T>G (p.Ile713Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: SLC26A4 c.2139T>G (p.Ile713Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251288 control chromosomes, predominantly at a frequency of 0.0095 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literature as a benign variation supported by the Deafness Variation Database (example, Azaiez_2018), to our knowledge, no occurrence of c.2139T>G in individuals affected with Pendred Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (Dec 28, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Pendred syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000796686.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 19509082‚ 25262649
Likely benign (May 31, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000341821.4 First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC26A4 Number of individuals with the variant: 1 Sex: mixed
Benign (May 07, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060130.6 First in ClinVar: May 03, 2013 Last updated: May 03, 2018	Comment: Ile713Met in Exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (27/3736) of … (more) Ile713Met in Exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (27/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143708308). (less) Number of individuals with the variant: 7
Benign (Aug 07, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730598.3 First in ClinVar: Apr 09, 2018 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 30245029, 25262649, 19509082)
Benign (Jan 31, 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: SCV001093221.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Jul 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004155768.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: SLC26A4: BS1, BS2 Number of individuals with the variant: 1
Benign (Apr 16, 2020)	no assertion criteria provided Method: clinical testing	Pendred syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001463982.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (Jan 27, 2020)	no assertion criteria provided Method: clinical testing	SLC26A4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004740030.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

Variant summary: SLC26A4 c.2139T>G (p.Ile713Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251288 control chromosomes, predominantly at a frequency of 0.0095 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literature as a benign variation supported by the Deafness Variation Database (example, Azaiez_2018), to our knowledge, no occurrence of c.2139T>G in individuals affected with Pendred Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Comment:

Ile713Met in Exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (27/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143708308).

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
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes.	Azaiez H	American journal of human genetics	2018	PMID: 30245029
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.	Shearer AE	American journal of human genetics	2014	PMID: 25262649
Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss.	Dai P	Physiological genomics	2009	PMID: 19509082
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC26A4	-	-	-	-

Text-mined citations for rs143708308 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000441.2(SLC26A4):c.2139T>G (p.Ile713Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143708308 ...