NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser) AND Autosomal recessive nonsyndromic hearing loss 4

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 5, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV001004634.14

Allele description [Variation Report for NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser)]

NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser)

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.1061T>C (p.Phe354Ser)

Other names:

NM_000441.2(SLC26A4):c.1061T>C

HGVS:

NC_000007.14:g.107689112T>C
NG_008489.1:g.33478T>C
NM_000441.2:c.1061T>CMANE SELECT
NP_000432.1:p.Phe354Ser
NC_000007.13:g.107329557T>C
NM_000441.1:c.1061T>C
c.1061T>C

Protein change:

F354S

Links:

dbSNP: rs111033243

NCBI 1000 Genomes Browser:

rs111033243

Molecular consequence:

NM_000441.2:c.1061T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 4 (DFNB4)
Synonyms:: NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 4; DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC; Nonsyndromic enlarged vestibular aqueduct (NSEVA); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010933; MedGen: C3538946; Orphanet: 90636; OMIM: 600791

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000994879	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center See additional submitters The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University	no assertion criteria provided	other (Aug 20, 2019)	germline	literature only, in vitro	PubMed (13) [See all records that cite these PMIDs] 15355436, 19017801, 19509082, 21045265, 22116359, 25262649, 26226137, 26764160, 27771369, 28444304, 27861301, 30245029, 31599023
SCV001321509	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21045265, 22116359, 16570074, 19017801, 19509082 Citation Link,
SCV002027118	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000994879

National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center

See additional submitters

no assertion criteria provided

other
(Aug 20, 2019)

germline

literature only, in vitro

PubMed (13)
[See all records that cite these PMIDs]

SCV001321509

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002027118

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Sep 5, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research, in vitro
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only, clinical testing

Citations

PubMed

Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity.

Blons H, Feldmann D, Duval V, Messaz O, Denoyelle F, Loundon N, Sergout-Allaoui A, Houang M, Duriez F, Lacombe D, Delobel B, Leman J, Catros H, Journel H, Drouin-Garraud V, Obstoy MF, Toutain A, Oden S, Toublanc JE, Couderc R, Petit C, Garabédian EN, et al.

Clin Genet. 2004 Oct;66(4):333-40.

PubMed [citation]

PMID:: 15355436

Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.

Shearer AE, Eppsteiner RW, Booth KT, Ephraim SS, Gurrola J 2nd, Simpson A, Black-Ziegelbein EA, Joshi S, Ravi H, Giuffre AC, Happe S, Hildebrand MS, Azaiez H, Bayazit YA, Erdal ME, Lopez-Escamez JA, Gazquez I, Tamayo ML, Gelvez NY, Leal GL, Jalas C, Ekstein J, et al.

Am J Hum Genet. 2014 Oct 2;95(4):445-53. doi: 10.1016/j.ajhg.2014.09.001. Epub 2014 Sep 25.

PubMed [citation]

PMID:: 25262649
PMCID:: PMC4185121

See all PubMed Citations (16)

Details of each submission

From National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, SCV000994879.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (13)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (13)

Description

Benign effect in vitro experiment

#	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
2	germline	yes	not provided	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001321509.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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

From Genome-Nilou Lab, SCV002027118.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From King Laboratory, University of Washington, SCV002059886.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

SLC26A4 c.1061T>C, p.F354S alters a highly conserved residue of SLC26A4 that is predicted to weaken a transmembrane domain. The variant is homozygous in 4 Palestinian children with pre-lingual severe to profound hearing loss (Abu Rayyan 2020). It is present in 5 of 1300 Palestinian controls, as a heterozygote, and present in 164/282612 alleles on gnomAD, all heterozygotes.

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002059886	King Laboratory, University of Washington	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Abu Rayyan A et al. (Proc Natl Acad Sci U S A 2020))	Likely pathogenic (Aug 1, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002059886

King Laboratory, University of Washington

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Abu Rayyan A et al. (Proc Natl Acad Sci U S A 2020))

Likely pathogenic
(Aug 1, 2020)

germline

research

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

Last Updated: Nov 3, 2024

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