NM_000441.2(SLC26A4):c.1541A>G (p.Gln514Arg) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 7, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000320959.11

Allele description [Variation Report for NM_000441.2(SLC26A4):c.1541A>G (p.Gln514Arg)]

NM_000441.2(SLC26A4):c.1541A>G (p.Gln514Arg)

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.1541A>G (p.Gln514Arg)

HGVS:

NC_000007.14:g.107696036A>G
NG_008489.1:g.40402A>G
NM_000441.2:c.1541A>GMANE SELECT
NP_000432.1:p.Gln514Arg
NC_000007.13:g.107336481A>G
NM_000441.1:c.1541A>G
O43511:p.Gln514Arg
c.1541A>G

Protein change:

Q514R

Links:

UniProtKB: O43511#VAR_027241; dbSNP: rs111033316

NCBI 1000 Genomes Browser:

rs111033316

Molecular consequence:

NM_000441.2:c.1541A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329521	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 7, 2024)	germline	clinical testing	Citation Link,
SCV001225432	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15689455, 25394566, 26969326, 19204907, 18285825, 19017801, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329521

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 7, 2024)

germline

clinical testing

Citation Link,

SCV001225432

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities.

Pryor SP, Madeo AC, Reynolds JC, Sarlis NJ, Arnos KS, Nance WE, Yang Y, Zalewski CK, Brewer CC, Butman JA, Griffith AJ.

J Med Genet. 2005 Feb;42(2):159-65. No abstract available.

PubMed [citation]

PMID:: 15689455
PMCID:: PMC1735974

Evaluation of genotype-phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome.

Soh LM, Druce M, Grossman AB, Differ AM, Rajput L, Bitner-Glindzicz M, Korbonits M.

Eur J Endocrinol. 2015 Feb;172(2):217-26. doi: 10.1530/EJE-14-0679. Epub 2014 Nov 13.

PubMed [citation]

PMID:: 25394566

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000329521.8

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

Description

Published functional studies demonstrate mislocalization of the SLC26A4 protein, however the effect on ion transport was not assessed (PMID: 19204907); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33199029, 23555729, 26969326, 25394566, 19318451, 15689455, 19204907, 34515852, 38426810)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225432.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 514 of the SLC26A4 protein (p.Gln514Arg). This variant is present in population databases (rs111033316, gnomAD 0.01%). This missense change has been observed in individuals with Pendred syndrome (PMID: 15689455, 25394566, 26969326). ClinVar contains an entry for this variant (Variation ID: 43511). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19204907). This variant disrupts the p.Gln514 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18285825, 19017801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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: Oct 26, 2024

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