NM_000441.2(SLC26A4):c.2T>C (p.Met1Thr) AND Rare genetic deafness

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 22, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000036489.7

Allele description [Variation Report for NM_000441.2(SLC26A4):c.2T>C (p.Met1Thr)]

NM_000441.2(SLC26A4):c.2T>C (p.Met1Thr)

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.2T>C (p.Met1Thr)

HGVS:

NC_000007.14:g.107661643T>C
NG_008489.1:g.6009T>C
NM_000441.2:c.2T>CMANE SELECT
NP_000432.1:p.Met1Thr
NC_000007.13:g.107302088T>C
NM_000441.1:c.2T>C
NR_028137.1:n.156A>G
c.2T>C
p.Met1?

Protein change:

M1T

Links:

dbSNP: rs111033302

NCBI 1000 Genomes Browser:

rs111033302

Molecular consequence:

NM_000441.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000441.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_028137.1:n.156A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Rare genetic deafness
Identifiers:: MedGen: C5680250; Orphanet: 96210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060144	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Nov 22, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 14679580, 19204907, 19509082, 16950989, 15099345, 21961810, 24224479, 17876604, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060144

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Nov 22, 2017)

germline

clinical testing

PubMed (9)
[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	not provided	3	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pendred syndrome and DFNB4-mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of eleven novel mutations.

Prasad S, Kölln KA, Cucci RA, Trembath RC, Van Camp G, Smith RJ.

Am J Med Genet A. 2004 Jan 1;124A(1):1-9.

PubMed [citation]

PMID:: 14679580

Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?

Choi BY, Stewart AK, Madeo AC, Pryor SP, Lenhard S, Kittles R, Eisenman D, Kim HJ, Niparko J, Thomsen J, Arnos KS, Nance WE, King KA, Zalewski CK, Brewer CC, Shawker T, Reynolds JC, Butman JA, Karniski LP, Alper SL, Griffith AJ.

Hum Mutat. 2009 Apr;30(4):599-608. doi: 10.1002/humu.20884.

PubMed [citation]

PMID:: 19204907
PMCID:: PMC2663020

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060144.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (9)

Description

The c.2T>C (p.Met1?) variant in SLC26A4 has been reported in at least 6 individu als with hearing loss and EVA, all of whom were compound heterozygous (Shears 20 04, Gardner 2006, Dai 2009, Choi 2009, Huang 2011, Ladsous 2014, LMM data). It h as been identified in 0.01% (14/87438) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033302). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency for recessive hearing loss . This variant affects the translation initiation start codon (ATG) and is there fore predicted to disrupt translation. In vitro functional studies provide some evidence that the c.2T>C variant may impact protein function (Choi 2009). Additi onally, a different variant in the translation initiation start codon (c.3G>C) h as also been reported in an individual with hearing loss and EVA, supporting tha t changes to this codon are not tolerated. In summary, this variant meets crite ria to be classified as pathogenic for hearing loss in an autosomal recessive ma nner based on the predicted impact of the variant and multiple occurrences with pathogenic SLC26A4 variants in individuals with hearing loss. ACMG/AMP Criteria applied: PVS1; PM3_VeryStrong; PP4.

#	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		3	not provided	3	not provided

Last Updated: Oct 26, 2024

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