NM_000441.2(SLC26A4):c.1174A>T (p.Asn392Tyr) AND not provided

Clinical significance:Pathogenic (Last evaluated: Aug 21, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000657916.3

Allele description [Variation Report for NM_000441.2(SLC26A4):c.1174A>T (p.Asn392Tyr)]

NM_000441.2(SLC26A4):c.1174A>T (p.Asn392Tyr)

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.1174A>T (p.Asn392Tyr)
HGVS:
  • NC_000007.14:g.107690148A>T
  • NG_008489.1:g.34514A>T
  • NM_000441.2:c.1174A>TMANE SELECT
  • NP_000432.1:p.Asn392Tyr
  • NC_000007.13:g.107330593A>T
  • NM_000441.1:c.1174A>T
  • p.Asn392Tyr
Protein change:
N392Y
Links:
dbSNP: rs201562855
NCBI 1000 Genomes Browser:
rs201562855
Molecular consequence:
  • NM_000441.2:c.1174A>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000779683GeneDxcriteria provided, single submitter
Pathogenic
(May 10, 2018)
germlineclinical testing

Citation Link,

SCV001224335Invitaecriteria provided, single submitter
Pathogenic
(Aug 21, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation analysis of SLC26A4 in mainland Chinese patients with enlarged vestibular aqueduct.

Reyes S, Wang G, Ouyang X, Han B, Du LL, Yuan HJ, Yan D, Dai P, Liu XZ.

Otolaryngol Head Neck Surg. 2009 Oct;141(4):502-8. doi: 10.1016/j.otohns.2009.07.004.

PubMed [citation]
PMID:
19786220
PMCID:
PMC3309400

Extremely discrepant mutation spectrum of SLC26A4 between Chinese patients with isolated Mondini deformity and enlarged vestibular aqueduct.

Huang S, Han D, Yuan Y, Wang G, Kang D, Zhang X, Yan X, Meng X, Dong M, Dai P.

J Transl Med. 2011 Sep 30;9:167. doi: 10.1186/1479-5876-9-167.

PubMed [citation]
PMID:
21961810
PMCID:
PMC3204245
See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000779683.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The N392Y missense variant has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Huang et al., 2011; Luo et al., 2017; Reyes et al., 2009). Functional studies report that N392Y resulted in the change of intracellular localization of the protein and the loss of anion transporter activity (Ishihara et al., 2010). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we consider this to be a pathogenic variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001224335.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces asparagine with tyrosine at codon 392 of the SLC26A4 protein (p.Asn392Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs201562855, ExAC 0.01%). This variant has been observed in individual(s) with nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 19786220, 21961810, 17718863). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446453). This variant has been reported to affect SLC26A4 protein function (PMID: 20826203). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2021

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