NM_000441.2(SLC26A4):c.2291C>T (p.Thr764Met) AND Pendred syndrome

Clinical significance:Uncertain significance (Last evaluated: Sep 28, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000346954.3

Allele description [Variation Report for NM_000441.2(SLC26A4):c.2291C>T (p.Thr764Met)]

NM_000441.2(SLC26A4):c.2291C>T (p.Thr764Met)

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.2291C>T (p.Thr764Met)
Other names:
NM_000441.1(SLC26A4):c.2291C>T(p.Thr764Met); NM_000441.1(SLC26A4):c.2291C>T
HGVS:
  • NC_000007.14:g.107712594C>T
  • NG_008489.1:g.56960C>T
  • NM_000441.2:c.2291C>TMANE SELECT
  • NP_000432.1:p.Thr764Met
  • NC_000007.13:g.107353039C>T
  • NM_000441.1:c.2291C>T
  • c.2291C>T
Protein change:
T764M
Links:
dbSNP: rs150597240
NCBI 1000 Genomes Browser:
rs150597240
Molecular consequence:
  • NM_000441.2:c.2291C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Pendred syndrome (PDS)
Synonyms:
HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 2B; THYROID DYSHORMONOGENESIS 2B; THYROID HORMONOGENESIS, GENETIC DEFECT IN, 2B; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010134; MedGen: C0271829; Orphanet: 705; OMIM: 274600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000466110Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000840520ClinGen Hearing Loss Variant Curation Expert Panelreviewed by expert panel
Uncertain significance
(Sep 28, 2018)
germlinecuration

Citation Link,

SCV001459945Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000466110.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV000840520.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The allele frequency of the p.Thr764Met variant in SLC26A4 is 0.01% (3/24024) of African alleles and 0.007% (9/126592) of European (Non-Finnish) alleles by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). However, rarity/absence alone does not support a pathogenic classification. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_P.

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

From Natera, Inc., SCV001459945.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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