Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser)

CA132656

43492 (ClinVar)

Gene: SLC26A4
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b48ee315-8429-4ca4-bd90-2fedff035f46

HGVS expressions

NM_000441.2:c.1061T>C
NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser)
NC_000007.14:g.107689112T>C
CM000669.2:g.107689112T>C
NC_000007.13:g.107329557T>C
CM000669.1:g.107329557T>C
NC_000007.12:g.107116793T>C
NG_008489.1:g.33478T>C
ENST00000644269.2:c.1061T>C
ENST00000265715.7:c.1061T>C
NM_000441.1:c.1061T>C

Likely Benign

Met criteria codes 2
BS1_Supporting BS3
Not Met criteria codes 19
PS1 PS3 BA1 PP4 PP1 PP3 PP2 PM1 PM5 PM4 PM3 PM2 PVS1 BS4 BP3 BP2 BP4 BP1 BP7

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.1061T>C variant in SLC26A4 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 354 (p.Phe354Ser). The filtering allele frequency (95% CI) in gnomAD v.2.1.1 was 0.1102% (153/251206 alleles, 6 homozygotes) in Latino/Admixed American population which meets the AR threshold (≥0.07%) for BS1_P. Although the REVEL computational prediction analysis tool produced a score of 0.955, PP3 was not applied. It was observed in 3 probands with sensorineural hearing loss, however they were not scored due to the high FAF in gnomAD (PMID: 26226137, 32747562, 27861301). Functional studies have shown that this variant does not affect the ability of the protein to mediate iodide and chloride transport (PMID:22116359, 31599023) meeting BS3. In summary, this variant is likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: BS3, BS1_P (ClinGen Hearing Loss VCEP specifications version 2; 11/28/2023)
Met criteria codes
BS1_Supporting
The filtering allele frequency (95% CI) in gnomAD v.2.1.1 was 0.1102% (153/251206 alleles, 6 homozygotes) in Latino/Admixed American population
BS3
Functional assays show that this variant does not affect the ability of the protein to mediate iodide and chloride transport (PMID:22116359, 31599023)
Iodine transport activity assay of pendrin F354S was indistinguishable from WT, indicating that this mutation does not affect the ability of the protein to mediate iodide transport. The Cl−/OH− exchange activity of this variant was also not affected PubMed:22116359
Anion transport assays (I−/Cl− and Cl−/HCO3− antiport assay) of the variant showed WT-like transport activities PubMed:31599023
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Variant segregated in 4 members in a family with SNHL but was not scored due to high FAF in gnomAD and functional assays showing benign evidence
PP3
REVEL score was 0.955, but PP3 was not applied due to high allele frequency in gnomAD and functional assays showing benign evidence
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Observed in 3 probands with sensorineural hearing loss (PMID: 26226137, 32747562, 27861301), however they were not scored due to the high FAF in gnomAD and functional assays showing benign evidence
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-11-28
Published on: 2024-04-01
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