NM_000441.2(SLC26A4):c.2090-1G>A AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 3, 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:: RCV001052316.7

Allele description [Variation Report for NM_000441.2(SLC26A4):c.2090-1G>A]

NM_000441.2(SLC26A4):c.2090-1G>A

Genes:

LOC123956210:Sharpr-MPRA regulatory region 3291 [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.2090-1G>A

HGVS:

NC_000007.14:g.107710053G>A
NG_008489.1:g.54419G>A
NG_078404.1:g.290G>A
NM_000441.2:c.2090-1G>AMANE SELECT
NC_000007.13:g.107350498G>A
NM_000441.1:c.2090-1G>A

Links:

dbSNP: rs1455597424

NCBI 1000 Genomes Browser:

rs1455597424

Molecular consequence:

NM_000441.2:c.2090-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001216521	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 16, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28964290, 16199547, 16283880, 25394566, 26252218, 26445815, 28492532
SCV005327246	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 3, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001216521

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 16, 2022)

germline

clinical testing

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

SCV005327246

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 3, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Novel pathogenic variants underlie SLC26A4-related hearing loss in a multiethnic cohort.

Cengiz FB, Yilmazer R, Olgun L, Sennaroglu L, Kirazli T, Alper H, Olgun Y, Incesulu A, Atik T, Huesca-Hernandez F, Domínguez-Aburto J, González-Rosado G, Hernandez-Zamora E, Arenas-Sordo ML, Menendez I, Orhan KS, Avci H, Mahdieh N, Bonyadi M, Foster J 2nd, Duman D, Ozkinay F, et al.

Int J Pediatr Otorhinolaryngol. 2017 Oct;101:167-171. doi: 10.1016/j.ijporl.2017.08.006. Epub 2017 Aug 8.

PubMed [citation]

PMID:: 28964290
PMCID:: PMC5679420

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001216521.5

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 553831). Disruption of this splice site has been observed in individual(s) with enlarged vestibular aqueduct (PMID: 28964290). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 18 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815).

#	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 GeneDx, SCV005327246.1

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

Description

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34628810, 28964290)

#	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

Last Updated: Oct 8, 2024

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