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: 2019-02-25

Published on: 2019-07-17

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
ENST00000265715.7:c.1069G>A

Benign

• Met criteria codes: PP3 BA1

• Not Met criteria codes: PS1 PS4 PM5 PM1 BP5 BP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Pendred syndrome variants (BA1). The REVEL computational prediction analysis tool produces a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1.

Met criteria codes

• PP3: The REVEL computational prediction analysis tool produced a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own.
• BA1: The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Pendred syndrome variants (BA1).

Not Met criteria codes

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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.
• PM5: 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
• 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.
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline