NM_000441.2(SLC26A4):c.964A>G (p.Asn322Asp) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Apr 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000036514.6

Allele description [Variation Report for NM_000441.2(SLC26A4):c.964A>G (p.Asn322Asp)]

NM_000441.2(SLC26A4):c.964A>G (p.Asn322Asp)

Gene:

SLC26A4:solute carrier family 26 member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q22.3

Genomic location:

Preferred name:

NM_000441.2(SLC26A4):c.964A>G (p.Asn322Asp)

HGVS:

NC_000007.14:g.107683500A>G
NG_008489.1:g.27866A>G
NM_000441.2:c.964A>GMANE SELECT
NP_000432.1:p.Asn322Asp
NC_000007.13:g.107323945A>G
NM_000441.1:c.964A>G
c.964A>G

Protein change:

N322D

Links:

dbSNP: rs143002265

NCBI 1000 Genomes Browser:

rs143002265

Molecular consequence:

NM_000441.2:c.964A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060169	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (May 7, 2012)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003928979	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Apr 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17309986, 23401162, 21704276 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060169

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(May 7, 2012)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003928979

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Apr 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	3	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct.

Madden C, Halsted M, Meinzen-Derr J, Bardo D, Boston M, Arjmand E, Nishimura C, Yang T, Benton C, Das V, Smith R, Choo D, Greinwald J.

Arch Otolaryngol Head Neck Surg. 2007 Feb;133(2):162-8. Erratum in: Arch Otolaryngol Head Neck Surg. 2007 Jun;133(6):607.

PubMed [citation]

PMID:: 17309986

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060169.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

Asn322Asp in Exon 08 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (18/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143002265).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	3	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928979.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: SLC26A4 c.964A>G (p.Asn322Asp) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 250902 control chromosomes, predominantly at a frequency of 0.0044 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.964A>G has been reported in the literature, primarily as an uninformative genotype (i.e. zygosity not specified), in individuals affected with hearing loss/enlarged vestibular aqueduct, without strong evidence for causality (e.g. Madden_2007, Chen_2011, Greinwald_2013). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21704276, 23401162, 17309986). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=3), or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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