NM_000441.2(SLC26A4):c.2219G>T (p.Gly740Val) AND Pendred syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 13, 2024
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:: RCV001164905.10

Allele description [Variation Report for NM_000441.2(SLC26A4):c.2219G>T (p.Gly740Val)]

NM_000441.2(SLC26A4):c.2219G>T (p.Gly740Val)

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.2219G>T (p.Gly740Val)

HGVS:

NC_000007.14:g.107710183G>T
NG_008489.1:g.54549G>T
NM_000441.2:c.2219G>TMANE SELECT
NP_000432.1:p.Gly740Val
NC_000007.13:g.107350628G>T
NM_000441.1:c.2219G>T
c.2219G>T

Protein change:

G740V

Links:

dbSNP: rs111033310

NCBI 1000 Genomes Browser:

rs111033310

Molecular consequence:

NM_000441.2:c.2219G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001327066	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23965030, 20597900 Citation Link,
SCV001459943	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002027517	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002555750	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 13, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 25788563, 25991456, 30240412, 30245029, 23804846, 18285825, 16570074, 23401162, 23965030, 20597900, 36833263 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Deafness gene variations in a 1120 nonsyndromic hearing loss cohort: molecular epidemiology and deafness mutation spectrum of patients in Japan.

Nishio SY, Usami S.

Ann Otol Rhinol Laryngol. 2015 May;124 Suppl 1:49S-60S. doi: 10.1177/0003489415575059. Epub 2015 Mar 18.

PubMed [citation]

PMID:: 25788563

See all PubMed Citations (12)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001327066.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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 Natera, Inc., SCV001459943.1

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

#	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, SCV002027517.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002555750.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: SLC26A4 c.2219G>T (p.Gly740Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251252 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0003 vs 0.0035), allowing no conclusion about variant significance. c.2219G>T has been reported in the literature in individuals affected with Hearing loss (Albert_2006, Tang_2015, Baldyga_2023). These data indicate that the variant is likely to be associated with disease. 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: 25788563, 25991456, 30240412, 30245029, 23804846, 18285825, 16570074, 23401162, 23965030, 20597900, 36833263).ClinVar contains an entry for this variant (Variation ID: 43545). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: Nov 3, 2024

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