Variant: NM_000441.1(SLC26A4):c.349C>T

CA132727

43555 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 67c2f97e-385f-494a-b06e-701135ace536

HGVS expressions

NM_000441.1:c.349C>T
NM_000441.1(SLC26A4):c.349C>T
NC_000007.14:g.107672182C>T
CM000669.2:g.107672182C>T
NC_000007.13:g.107312627C>T
CM000669.1:g.107312627C>T
NC_000007.12:g.107099863C>T
NG_008489.1:g.16548C>T
ENST00000644269.2:c.349C>T
ENST00000265715.7:c.349C>T
ENST00000440056.1:c.349C>T
NM_000441.2:c.349C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence, Benign"

• Met criteria codes: PM3_Very Strong BS3_Supporting PP4 PP3 PP1_Strong BA1

• Not Met criteria codes: PVS1 PS2 PS4 PS3 PS1 PP2 PM6 PM2 PM1 PM4 PM5 BS2 BS4 BS1 BP2 BP3 BP1 BP4 BP5 BP7

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 c.349C>T variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 117. The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, 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 hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel (LMM) (PP4). The variant has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence (BS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VS, PP1_S, PP4, PP3, BS3_P (Hearing Loss VCEP specifications version 2; 11/22/2022).

Met criteria codes

• PM3_Very Strong: This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong).
• BS3_Supporting: A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence (BS3_Supporting).
• PP4: This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel.
• PP3: The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3).
• PP1_Strong: The variant has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1).
• BA1: The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, 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 hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification.

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant was found in 3 patients in the published literature. It has also been reported in ClinVar in another case from Prof. Karen Avraham @ Tel Aviv Univ.'s lab with congenital profound HL. There are 9 cases in the LMM database with HL/HL + EVA and this variant, however one of them also has a pathogenic AD KCNQ4 variant so this proband was not counted. Reardon 1/114 alleles in HL+ EVA cohort Albert 1/218 alleles in HL + EVA cohort Sloan Heggen: 1/2238 in HL cohort LMM internal 5/3884 SLC26A4 tested alleles as of last NVA 8/6454 Alleles Tested in HL/HL+EVA cohorts vs. gnomAD: 22/126640 European alleles in gnomAD. AND 52/10150 Ashkenazi alleles in gnomAD = 74/136790 ~ 67/123456 In contingency table: 8 to 6446 vs 67 to 123389 p = 0.0448. Applied Moderate evidence. Note: if you add in the internal proband with the KCNQ4 variant the significance is higher but it doesn't seem logical to use a proband with alternate cause in this exercise. Also, Karen Avraham's proband was not counted here because the denominator is unknown. I removed this criteria (was previously scored as PS4_Moderate), but we did not use it in our final classification listed in the Human Mutation manuscript. - Andrea 7.31.18
• PS3: 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
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: 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
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: There is a reported genotype of a compund het case with the c.578C>T variant that was interpreted as pathogenic by a zero star submitter, but there are no other missense variants reported at this codon in ClinVar.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: There are 2 family members in LMM's internal data who are unaffected but are heterozygous for the p.Leu117Phe variant. However, they don't have the other variant that is in trans in the affected individual.
• BS1: 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
• BP1: z=-3.23
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: While this variant has been suspected to have an alternate cause in patients due to its lack of known functional implications and the patient in Taylor et al. 2002's lack of thyroid dysfunction at age 18 yr, but a second variant was not identified. In an LMM case, there was a patient without EVA that had this variant as well as a heterozygous pathogenic c.459delC KCNQ4 variant which is known to cause AD HL. Therefore, BP5 could be applied here. RS 9/18/18 After review, this criteria has been determined not met.
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-11-22

Published on: 2023-01-25