Variant: NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)

CA274070

188878 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: cfc9189b-83ef-4fee-9391-68daefe50667

HGVS expressions

NM_000441.2:c.554G>C
NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)
NM_000441.1:c.554G>C
ENST00000265715.7:c.554G>C
NC_000007.14:g.107674302G>C
CM000669.2:g.107674302G>C
NC_000007.13:g.107314747G>C
CM000669.1:g.107314747G>C
NC_000007.12:g.107101983G>C
NG_008489.1:g.18668G>C

Likely Pathogenic

• Met criteria codes: PS3_Supporting PM2_Supporting PP3 PP4 PM3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.554G>A (p.Arg185Thr) variant in SLC26A4 was present in 0.03287% (1/3042) of South Asian alleles in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as two probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650). It was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3, PS3_Supporting, PM2_Supporting, PP3, PP4.

Met criteria codes

• PS3_Supporting: Fluorometric assay in COS-7 cells transfected with this variant demonstrated impaired chloride/iodide transport (PMID: 22285650).
• PM2_Supporting: Present in 0.01471% (19/129168) of non-Finnish European alleles in gnomAD v2.1.1. In v3, present in 0.03287% (1/3042) of South Asian alleles.
• PP3: REVEL score 0.876. Alamut does not predict an impact to splicing. Only 1 animal in the UCSC database has an alternate aa at this site (Atlantic cod, G).
• PP4: 1 proband with this variant had unilateral hearing loss and EVA (PMID: 24051746). Multiple other probands did not have other pathogenic variants identified in SLC26A4, but had progressive HL, bilateral EVA, and goiter consistent with classical Pendred syndrome (PMID: 20597900, 31387071). Additionally, one proband had a diagnosis of Pendred syndrome, but no second variant was identified and detailed phenotyping was not available (PMID: 31387071).
• PM3: 1 PM3 point was assigned to a proband with unilateral hearing loss and EVA with the c.890delC (p.Pro297fs) variant in SLC26A4 in trans (PMID: 24051746). Additionally, 0.25 points each were assigned to 2 probands without second variants identified but with clinical presentations consistent with classical Pendred syndrome (PMID: 20597900, 22285650). One other proband had a diagnosis of Pendred syndrome, but no second variant was identified and detailed phenotyping was not available (PMID: 31387071).

Approved on: 2020-06-24

Published on: 2020-06-26