Variant: NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu)

CA253316

4842 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: fd54e511-37fc-437e-bf54-4757947ec10f

Approved on: 2020-08-25

Published on: 2020-08-26

HGVS expressions

NM_000441.2:c.1003T>C
NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu)
NC_000007.14:g.107689054T>C
CM000669.2:g.107689054T>C
NC_000007.13:g.107329499T>C
CM000669.1:g.107329499T>C
NC_000007.12:g.107116735T>C
NG_008489.1:g.33420T>C
ENST00000644269.2:c.1003T>C
ENST00000265715.7:c.1003T>C
NM_000441.1:c.1003T>C

Uncertain Significance

• Met criteria codes: PP1 PP3 PP4 PS3_Supporting PM3_Very Strong BS1_Supporting

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1003T>C (p.Phe335Leu) variant has been identified in over 20 probands with Hearing loss, 6 of whom had a second pathogenic or suspected pathogenic variant in trans (PM3_VeryStrong; PMIDs: 19509082, 29293505, 25394566, 20668687, 20597900, 19426954, 19204907, 18285825, 17503324, 17357124, 17309986, 15689455, 14679580, 11317356, Laboratory for Molecular Medicine internal data). The variant has been reported to segregate with disease in one affected family member (PP1; PMID: 18285825). Multiple probands presented with hearing loss and enlarged vestibular aqueducts (EVA) which are highly specific to Pendred syndrome (PP4; PMIDs: 14679580, 18285825, 19509082, 25394566, Laboratory for Molecular Medicine internal data). The c.1003T>C (p.Phe335Leu) variant was present in 0.203% (76/30612 CI 95%) of South Asian alleles in gnomAD v2.1.1, which is a high enough frequency apply BS1_Supporting. The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1_Supporting code will not contribute to the overall classification. A functional study demonstrates that the p.Phe335Leu variant may impact protein function (PS3_Supporting; PMID: 19204907). Finally, the REVEL computational prediction analysis tool produced a score of 0.828, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PS3_Supporting, BS1_Supporting, PP1, PP3, PP4.

Met criteria codes

• PP1: PMID: 18285825
• PP3: REVEL: 0.858
• PP4: PMID: 18285825
• PS3_Supporting: PMID: 19204907
• PM3_Very Strong: 6 compound het cases
• BS1_Supporting: 0.203% (76/30612 CI 95%) of South Asian alleles in gnomAD v2.1.1