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.919-2A>G

CA261445

4840 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: cc6044de-e514-40c4-8834-632466dc33f1
Approved on: 2018-09-20
Published on: 2019-07-17

HGVS expressions

NM_000441.1:c.919-2A>G
NM_000441.1(SLC26A4):c.919-2A>G
NC_000007.14:g.107683453A>G
CM000669.2:g.107683453A>G
NC_000007.13:g.107323898A>G
CM000669.1:g.107323898A>G
NC_000007.12:g.107111134A>G
NG_008489.1:g.27819A>G
ENST00000265715.7:c.919-2A>G
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Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 4
PP1_Strong PM3_Very Strong PVS1 BS1
Not Met criteria codes 19
PS1 PS3 PS4 PS2 BP7 BP5 BP4 BP3 BP2 BA1 PP3 PP4 PM2 PM6 PM4 PM5 PM1 BS4 BS2

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The filtering allele frequency of the c.919-2A>G variant in the SLC26A4 gene is 0.4% for East Asian chromosomes in the Genome Aggregation Database (91/18860 with 95% CI) , which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, the c.919-2A>G variant in SLC26A4 is predicted to cause the skipping of a biologically-relevant out-of-frame exon 8. This is then expected to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). Additionally, this variant has been detected in 16 patients with hearing loss in trans with more than 4 pathogenic variants (PM3_VeryStrong; PMID: 23151025). The c.919-2A>G variant in SLC26A4 has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; 10874637). Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PP1_Strong, PM3_VeryStrong, BS1.
Met criteria codes
PP1_Strong
In the Coucke et al. 1999 family, the variant segregated in at least 6 affected individuals and was heterozygous in 7 individuals. The LOD score of 4.49 is Strong segregation evidence.
The c.919-2A>G variant was observed as homozygous segregating in at least six affected individuals in a consanguineous Turkish family with prelingual deafness and goitre. Two additional affected family members were compound heterozygous for the splice variant and a missense c.1558T>G variant in SLC26A4. PubMed:10874637
PM3_Very Strong
16 Chinese SNHL probands are compound heterozygous for the c.919-2A>G and p.H723R variants in SLC26A4.
Retrospective review of 1065 Chinese probands with moderate-to-profound bilateral sensorineural hearing loss found 53 homozygous and 80 heterozygous for the c.919-2A>G variant. 16 individuals were compound het. for the pathogenic p.H723R variant in SLC26A4. PubMed:23151025
PVS1
Following the PVS1 table: splice site, predicted out-of-frame consequence, predicted to undergo NMD, exon not alternatively spliced from major or biologically relevant transcript.
BS1
The variant is observed in 0.4% (91/18860) East Asian chromosomes. This variant is on the exclusion list, therefore the BS1 code will not contribute to the overall classification.
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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
BP4
Computation prediction tools not applied when PVS1 is applied.
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
Retrospective review of 1065 Chinese probands with moderate-to-profound bilateral sensorineural hearing loss found 53 homozygous and 80 heterozygous for the c.919-2A>G variant. 16 individuals were compound het. for the pathogenic p.H723R variant in SLC26A4. PubMed:23151025
BA1
The variant is observed in 0.4% (91/18860) East Asian chromosomes. This variant is on the exclusion list, therefore the BS1 code will not contribute to the overall classification.
PP3
Computation prediction tools not applied when PVS1 is applied.
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The variant is observed in 0.4% (91/18860) East Asian chromosomes. This variant is on the exclusion list, therefore the BS1 code will not contribute to the overall classification.
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
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
BS4
The c.919-2A>G variant was observed as homozygous segregating in at least six affected individuals in a consanguineous Turkish family with prelingual deafness and goitre. Two additional affected family members were compound heterozygous for the splice variant and a missense c.1558T>G variant in SLC26A4. PubMed:10874637
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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