NM_000441.2(SLC26A4):c.147C>G (p.Ser49Arg) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jul 12, 2022
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:: RCV000221470.7

Allele description [Variation Report for NM_000441.2(SLC26A4):c.147C>G (p.Ser49Arg)]

NM_000441.2(SLC26A4):c.147C>G (p.Ser49Arg)

Genes:

SLC26A4-AS1:SLC26A4 antisense RNA 1 [Gene - HGNC]
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.147C>G (p.Ser49Arg)

HGVS:

NC_000007.14:g.107661788C>G
NG_008489.1:g.6154C>G
NM_000441.2:c.147C>GMANE SELECT
NP_000432.1:p.Ser49Arg
NC_000007.13:g.107302233C>G
NM_000441.1:c.147C>G
NM_000441.2(SLC26A4):c.147C>GMANE SELECT
NR_028137.1:n.11G>C

Protein change:

S49R

Links:

dbSNP: rs756969021

NCBI 1000 Genomes Browser:

rs756969021

Molecular consequence:

NM_000441.2:c.147C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_028137.1:n.11G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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GJC1[gene] (22)
ClinVar
Homo sapiens mRNA for FLJ00259 protein
Homo sapiens mRNA for FLJ00259 protein
gi|34526490|dbj|AK131073.1|

Nucleotide
Homo sapiens mRNA for KIAA1985 protein
Homo sapiens mRNA for KIAA1985 protein
gi|18916897|dbj|AB075865.1|

Nucleotide
Homo sapiens cDNA FLJ12893 fis, clone NT2RP2004165
Homo sapiens cDNA FLJ12893 fis, clone NT2RP2004165
gi|10434645|dbj|AK022955.1|

Nucleotide
gap junction gamma-1 protein isoform X1 [Homo sapiens]
gap junction gamma-1 protein isoform X1 [Homo sapiens]
gi|2462552252|ref|XP_054170617.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000270849	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Nov 5, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25149764, 24033266
SCV002570599	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 12, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25149764, 31599023, 25372295, 34545167, 31427586 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000270849

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Nov 5, 2015)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002570599

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 12, 2022)

germline

clinical testing

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

Citation Link

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	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

A rapid method for simultaneous multi-gene mutation screening in children with nonsyndromic hearing loss.

Du W, Cheng J, Ding H, Jiang Z, Guo Y, Yuan H.

Genomics. 2014 Oct;104(4):264-70. doi: 10.1016/j.ygeno.2014.07.009. Epub 2014 Aug 19.

PubMed [citation]

PMID:: 25149764

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000270849.3

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

Description

p.Ser49Arg in exon 2 of SLC26A4: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, >10 mammals have an Arginine (Arg) at this position.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570599.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: SLC26A4 c.147C>G (p.Ser49Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 141150 control chromosomes, predominantly at a frequency of 0.0038 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0038 vs 0.0035), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.147C>G has been reported in the literature in heterozygous individuals affected with non-syndromic hearing loss, congenital hypothyroidism, and Pendred Syndrome (e.g. Du_2014, Zhao_2014, Ideura_2019, Zhang_2022), however without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. Functional studies have found the variant has little to no effect on protein expression, membrane localization, and ion transport activity when compared with the wild-type protein (e.g. Wasano_2020, Zhang_2022). Five ClinVar submitters including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Sep 29, 2024

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