NM_000441.1(SLC26A4):c.349C>T AND Rare genetic deafness

Clinical significance:Likely pathogenic (Last evaluated: Jul 8, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000036491.4

Allele description [Variation Report for NM_000441.1(SLC26A4):c.349C>T]

NM_000441.2(SLC26A4):c.349C>T (p.Leu117Phe)

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.349C>T (p.Leu117Phe)
Other names:
NM_000441.1(SLC26A4):c.349C>T(p.Leu117Phe); NM_000441.1(SLC26A4):c.349C>T
HGVS:
  • NC_000007.14:g.107672182C>T
  • NG_008489.1:g.16548C>T
  • NM_000441.2:c.349C>TMANE SELECT
  • NP_000432.1:p.Leu117Phe
  • NC_000007.13:g.107312627C>T
  • NM_000441.1:c.349C>T
  • O43511:p.Leu117Phe
  • c.349C>T
Protein change:
L117F
Links:
UniProtKB: O43511#VAR_021647; dbSNP: rs145254330
NCBI 1000 Genomes Browser:
rs145254330
Molecular consequence:
  • NM_000441.2:c.349C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functionally_normal [Sequence Ontology: SO:0002219]
Observations:
7

Condition(s)

Name:
Rare genetic deafness
Identifiers:
MedGen: CN826980; Orphanet: 96210

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000060146Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Jul 8, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown117not providednot providednot providedclinical testing

Citations

PubMed

Enlarged vestibular aqueduct: a radiological marker of pendred syndrome, and mutation of the PDS gene.

Reardon W, OMahoney CF, Trembath R, Jan H, Phelps PD.

QJM. 2000 Feb;93(2):99-104.

PubMed [citation]
PMID:
10700480

Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.

Taylor JP, Metcalfe RA, Watson PF, Weetman AP, Trembath RC.

J Clin Endocrinol Metab. 2002 Apr;87(4):1778-84.

PubMed [citation]
PMID:
11932316
See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000060146.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided11not providednot providedclinical testing PubMed (8)

Description

The p.Leu117Phe variant in SLC26A4 has been previously reported in 8 individuals with hearing loss, 6 of whom had enlarged vestibular aqueducts, and 5 of whom had a second SLC26A4 variant on the remaining allele (Reardon 2000, Albert 2006, Sloan-Heggen 2016, ClinVar SCV000282015.1, LMM unpublished data). This variant was classified as Likely Pathogenic on Sep 26, 2018 by the ClinGen-approved Hearing Loss expert panel (Variation ID 43555). This variant has also been reported in the homozygous state in 2 Ashkenazi Jewish families with hearing loss (Brownstein 2020, bioRxiv 2020.06.11.144790; doi: https://doi.org/10.1101/2020.06.11.144790). The variant segregated in 2 affected family members; however, one affected individual was heterozygous only for the variant. This variant is also present in 0.5% (54/10368) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145254330). However, given the lack of understanding of Pendred syndrome prevalence in the Ashkenazi Jewish population, this allele frequency was not considered strong enough conflicting evidence to counter the pathogenic evidence. Two in vitro functional study demonstrated that the variant did not impact localization of the protein to the cell membrane or iodide efflux capacity; however, not all ion transport functions of the mutant proteins were assessed (Taylor 2002, Wasano 2020). In addition, the leucine (Leu) residue at position 117 is highly conserved across mammals and distant species, suggesting that variants at this position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP criteria applied: PM3_VeryStrong, PP1, PP4, PP3, BS1, BS3_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided11not provided7not provided

Last Updated: Aug 27, 2021

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