Variant: NM_000441.1(SLC26A4):c.1069G>A (p.Ala357Thr)

CA132654

43491 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: ff136dc4-4d43-4577-beb7-70c08e9c04ab

Approved on: 2025-02-19

Published on: 2025-03-18

HGVS expressions

NM_000441.1:c.1069G>A
NM_000441.1(SLC26A4):c.1069G>A (p.Ala357Thr)
NC_000007.14:g.107689120G>A
CM000669.2:g.107689120G>A
NC_000007.13:g.107329565G>A
CM000669.1:g.107329565G>A
NC_000007.12:g.107116801G>A
NG_008489.1:g.33486G>A
ENST00000644269.2:c.1069G>A
ENST00000265715.7:c.1069G>A
NM_000441.2:c.1069G>A

Likely Benign

• Met criteria codes: BS1 PP3

• Not Met criteria codes: BA1 BP4 BP1 BP5 PS4 PS1 PP2 PM2 PM1 PM5

Expert Panel

Hearing Loss VCEP

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

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency of the c.1069G>A (p.Ala357Thr) variant in the SLC26A4 gene is 0.46% for African/African American chromosomes by gnomAD v4.1.0 (489/1613848 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL VCEP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.849, which is above the threshold necessary to apply PP3. The HL VCEP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in​ this case as computational scores are error prone, especially when predicting pathogenicity. In summary, the HL VCEP classified this variant as likely benign. (BS1, PP3; Clingen Hearing Loss VCEP Specifications Version 2; 02/19/2025).

Met criteria codes

• BS1: The filtering allele frequency of the c.1069G>A (p.Ala357Thr) variant in the SLC26A4 gene is 0.46% for African/African American chromosomes by gnomAD v4.1.0 (489/1613848 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL VCEP) for autosomal recessive hearing loss variants (BS1).
• PP3: The REVEL computational prediction analysis tool produced a score of 0.849, which is above the threshold necessary to apply PP3.

Not Met criteria codes

• BA1: The filtering allele frequency of the c.1069G>A (p.Ala357Thr) variant in the SLC26A4 gene is 0.46% for African/African American chromosomes by gnomAD v4.1.0 (489/1613848 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL VCEP) for autosomal recessive hearing loss variants (BS1).
• BP4: The REVEL computational prediction analysis tool produced a score of 0.849, which is above the threshold necessary to apply PP3.
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: One LMM internal case of an African American individual with congenital profound SNHL with hypothyroidism and a family history of HL is heterozygous for the p.Ala357Thr variant, and carries two other variants in SLC26A4 that were determined to be pathogenic and causative. BP5 not met however, because parental testing was not performed to confirm which variants are in cis/trans.
• PS4: The p.Ala357Thr variant was observed by the Partners Lab for Molecular Medicine as heterozygous in two individuals with hearing loss and related syndromes, with no other causative variants identified. A third case was identified with congenital profound sensorineural hearing loss with hypothyroidism and a family history of hearing loss, who carries the variant on one alleles. However, two other pathogenic SLC26A4 variants were observed in this proband and determined to be likely causative of disease. EGL Diagnostics observed the variant in heterozygosity in one hearing loss individual, however no other pathogenic or likely path. variants were identified.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The filtering allele frequency of the c.1069G>A (p.Ala357Thr) variant in the SLC26A4 gene is 0.46% for African/African American chromosomes by gnomAD v4.1.0 (489/1613848 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL VCEP) for autosomal recessive hearing loss variants (BS1).
• 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