Variant: NM_000441.2(SLC26A4):c.200C>G (p.Thr67Ser)

CA132691

43531 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: a2192ad9-6601-4289-bbb5-32f3b5814fd1

Approved on: 2020-09-22

Published on: 2020-09-24

HGVS expressions

NM_000441.2:c.200C>G
NM_000441.2(SLC26A4):c.200C>G (p.Thr67Ser)
NC_000007.14:g.107663331C>G
CM000669.2:g.107663331C>G
NC_000007.13:g.107303776C>G
CM000669.1:g.107303776C>G
NC_000007.12:g.107091012C>G
NG_008489.1:g.7697C>G
ENST00000644269.2:c.200C>G
ENST00000265715.7:c.200C>G
ENST00000440056.1:c.200C>G
NM_000441.1:c.200C>G

Likely Benign

• Met criteria codes: BP4 BP2

• Not Met criteria codes: PP1 PP3 PP4 PM2 PM3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.200C>G (p.Thr67Ser) variant in SLC26A4 was present in 0.011% (2/18,394) of East Asian alleles in gnomAD v2. Although this frequency is low enough to meet PM2_Supporting, the ClinGen Hearing Loss Expert Panel believes that the evidence that this variant is likely benign outweighs the low allele frequency in population databases. This variant has been observed in cis with p.Leu236Val, which the Hearing Loss Expert Panel has classified as likely pathogenic, in at least 6 probands (BP2; PMID: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6). It has been identified in at least 3 other probands with hearing loss with another pathogenic variant in SLC26A4 or in the homozygous state and segregated with disease in 1 additional family member (PMID: 18250610, 26969326, 22796198). Two probands with this variant displayed both sensorineural hearing loss and EVA, features highly specific for SLC26A4. Conservation analyses suggest that this variant may not impact the protein (BP4). Due to the possibility that the p.Thr67Ser and p.Leu236Val variants constitute a haplotype and the latter variant is driving pathogenicity, PM3, PP1, and PP4 were not applied. In summary, the p.Thr67Ser variant in SLC26A4 variant meets criteria to be considered likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BP2, BP4.

Met criteria codes

• BP4: REVEL score 0.426, however serine at this site is present in 9 mammals in the UCSC database (chimp, bushbaby, squirrel, naked mole rat, guinea pig, chinchilla, brush-tailed rat, opossum, Tasmanian devil). Not predicted to impact splicing.
• BP2: This variant has been observed in cis with p.Leu236Val, which the Hearing Loss Expert Panel has classified as likely pathogenic, in at least 6 probands (BP2; PMID: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6).

Not Met criteria codes

• PP1: Segregated with disease in 1 proband (PMID: 18250610). However, it was not clear whether this patient also carried the p.Leu236Val variant. The Hearing Loss Expert Panel believed that the evidence that this variant is likely benign outweighed this case.
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: Observed in 1 profound SNHL, EVA, multinodular goiter, and positive perchlorate test (PMID: 18250610). However, it was not clear whether this patient also carried the p.Leu236Val variant. The Hearing Loss Expert Panel believed that the evidence that this variant is likely benign outweighed this case.
• PM2: Seen in 0.01087% (2/18394) of East Asian chromosomes in gnomAD v2. Although this frequency is low enough to meet PM2_Supporting, the ClinGen Hearing Loss Expert Panel believes that the evidence that this variant is likely benign outweighs the low allele frequency in population databases.
• PM3: Observed in 3 probands with hearing loss: once in trans with c.919-2A>G (PMID: 18250610), once in the homozygous state (PMID: 26969326), and once with c.2168A>G (p.His723Arg) with phase unknown (PMID: 22796198). The homozygous proband was also found to carry p.Leu236Val (Molecular Otolaryngology and Renal Research Laboratories internal data). Due to the possibility that the other affected individuals also carried the p.Leu236Val variant, the Hearing Loss Expert Panel believed that the evidence that this variant is likely benign outweighed these cases.