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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  • See Evidence submitted by expert panel for details.

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

CA132654

43491 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: ff136dc4-4d43-4577-beb7-70c08e9c04ab

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 2
BA1 PP3
Not Met criteria codes 6
PM5 PM1 BP5 BP4 PS1 PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
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).
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.
Not Met criteria codes
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
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.
Approved on: 2019-02-25
Published on: 2019-07-17
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