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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000441.1(SLC26A4):c.365dupT (p.Ile124Tyrfs)

CA274422

189148 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: aecfa905-0f27-4b56-9e2b-3672bb807629
Approved on: 2018-09-10
Published on: 2019-07-17

HGVS expressions

NM_000441.1:c.365dupT
NM_000441.1(SLC26A4):c.365dupT (p.Ile124Tyrfs)
NM_000441.1:c.365dup
ENST00000265715.7:c.365dup
ENST00000440056.1:c.365dup
NC_000007.14:g.107672198dup
CM000669.2:g.107672198dup
NC_000007.13:g.107312643dup
CM000669.1:g.107312643dup
NC_000007.12:g.107099879dup
NG_008489.1:g.16564dup
More

Pathogenic

Met criteria codes 4
PP4 PM2 PVS1 PM3_Supporting
Not Met criteria codes 19
PP3 PP1 PM6 PM4 PM1 PM5 BA1 BS1 BS4 BS2 BP7 BP5 BP3 BP4 BP2 PS3 PS4 PS2 PS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The p.Ile124Tyrfs variant in SLC26A4 is predicted to cause a premature stop codon in biologically-relevant-exon 4/21 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Ile124fs variant is in 0.003% (1/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with the variant displayed features of enlarged vestibular aqueduct and Mondini malformation which are consistent with Pendred syndrome (PP4; PMID:15679828). This variant has been detected in 2 patients with hearing loss in trans with suspected pathogenic variants (PM3_P, PMID:15679828). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_P.
Met criteria codes
PP4
Subject 8, though they also carry a WT allele has a Mondini deformity which the HL Expert Panel has proposed to be a highly specific phenotype for the disease. Therefore PP4 can be applied here.
Subject 8, though they also carry a WT allele has a Mondini deformity which the HL Expert Panel has proposed to be a highly specific phenotype for the disease. Therefore PP4 can be applied here. PubMed:15679828
PM2
This variant is present in 0.003% (1/30782) South Asian alleles in gnomAD http://gnomad.broadinstitute.org/variant/7-107312637-C-CT
PVS1
This variant is predicted to cause a frameshift resulting in truncated or absent protein. It is not in the last or second to last exon or the last 50 nucleotides.
PM3_Supporting
Park et al. 2015. 2 probands with hearing loss and EVA, one compound het with the c.1707+5G>A variant, one het
The variant was detected in 2 probands. One proband had the c.365insT variant on one allele and the c.1707+5G>A variant on the other allele. This variant is classified as pathogenic in ClinVar by a submission from this publication, but it may not be classified as Likely Pathogenic based on our current criteria. Also, there is one proband with hearing loss and enlarged vestibule who has this variant in a heterozygous state with the wild type. This does not provide support for or against the variant's impact. PubMed:15679828
Not Met criteria codes
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No family data available
PM6
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
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
BA1
This variant is present in 0.003% (1/30782) South Asian alleles in gnomAD http://gnomad.broadinstitute.org/variant/7-107312637-C-CT
BS1
This variant is present in 0.003% (1/30782) South Asian alleles in gnomAD http://gnomad.broadinstitute.org/variant/7-107312637-C-CT
BS4
No family data available
BS2
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
BP5
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
The variant was detected in 2 probands. One proband had the c.365insT variant on one allele and the c.1707+5G>A variant on the other allele. This variant is classified as pathogenic in ClinVar by a submission from this publication, but it may not be classified as Likely Pathogenic based on our current criteria. Also, there is one proband with hearing loss and enlarged vestibule who has this variant in a heterozygous state with the wild type. This does not provide support for or against the variant's impact. PubMed:15679828
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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