NM_139319.3(SLC17A8):c.1120G>T (p.Ala374Ser) AND Autosomal dominant nonsyndromic hearing loss 25

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 22, 2020
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:: RCV000490397.8

Allele description [Variation Report for NM_139319.3(SLC17A8):c.1120G>T (p.Ala374Ser)]

NM_139319.3(SLC17A8):c.1120G>T (p.Ala374Ser)

Gene:

SLC17A8:solute carrier family 17 member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.1

Genomic location:

Preferred name:

NM_139319.3(SLC17A8):c.1120G>T (p.Ala374Ser)

HGVS:

NC_000012.12:g.100404104G>T
NG_021175.1:g.52026G>T
NM_001145288.2:c.970G>T
NM_139319.3:c.1120G>TMANE SELECT
NP_001138760.1:p.Ala324Ser
NP_647480.1:p.Ala374Ser
NC_000012.11:g.100797882G>T
NM_139319.2:c.1120G>T
p.Ala374Ser

Protein change:

A324S

Links:

dbSNP: rs138307707

NCBI 1000 Genomes Browser:

rs138307707

Molecular consequence:

NM_001145288.2:c.970G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139319.3:c.1120G>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

Condition(s)

Name:: Autosomal dominant nonsyndromic hearing loss 25
Synonyms:: Deafness, autosomal dominant 25
Identifiers:: MONDO: MONDO:0011568; MedGen: C1854158; Orphanet: 90635; OMIM: 605583

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267502	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 23967202, 25741868
SCV001271156	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV001366086	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 22, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267502

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 18, 2016)

germline

reference population

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

SCV001271156

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Likely benign
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV001366086

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 22, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
East Asian	germline	unknown	2	not provided	not provided	not provided	not provided	reference population
Muslim	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients.

Miyagawa M, Naito T, Nishio SY, Kamatani N, Usami S.

PLoS One. 2013;8(8):e71381. doi: 10.1371/journal.pone.0071381.

PubMed [citation]

PMID:: 23967202
PMCID:: PMC3742761

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

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	2	not provided	not provided	reference population	PubMed (2)

#	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		2	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001271156.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV001366086.1

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

Description

A heterozygous missense variation in exon 9 of the SLC17A5 gene that results in the amino acid substitution of Serine for Alanine at codon 374 was detected. The observed variant c.1120G>T (p.Ala374Ser) has a minor allele frequency of 0.2% and 0.12% in the 1000 genomes and ExAC databases respectively. The observed variant has previously been reported in a patient affected with deafness (Miyagawa et al. 2013) and is reported as a variant of uncertain significance in the ClinVar database. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.

#	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		1	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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