Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_206933.4:c.3547_3548del

48503 (ClinVar)

Gene: USH2A (HGNC:7399)

Condition: Usher syndrome (MONDO:0019501)

Inheritance Mode: Autosomal recessive inheritance

UUID: afc59df6-82ed-458e-aa96-f7857c925895

Approved on: 2022-11-22

Published on: 2023-02-06

HGVS expressions

NM_206933.4:c.3547_3548del

NM_206933.4(USH2A):c.3547_3548del (p.Ile1183fs)

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM2_Supporting

BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP1 BP4 BP2 PS1 PS3 PS2 PS4 BA1 PM4 PM5 PM1 PM3 PM6 PP2 PP3 PP1 PP4

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The p.Ile1183fs variant in USH2A introduces a premature stop codon in biologically-relevant-exon 17/72 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9624053, 25211151, 20497194). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00088% (1/113352 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). One proband with autosomal recessive retinitis pigmentosa was identified to be carrying the p.Ile1183fs variant with no variant reported in trans (PMID: 35266249). This variant was re-reviewed on 11/22/2022 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PVS1, PM2_P (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022).

PVS1

This variant introduces a premature stop codon in biologically-relevant-exon 17/72 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism

PM2_Supporting

Highest MAF is 0.00088% (1/113352) in gnomAD v.2.1.1

BS3

Variant has not been evaluated experimentally.

BS4

Variant has not been reported in patient or clinically-evaluated control populations.

BS1

Highest MAF is 0.00088% (1/113352) in gnomAD v.2.1.1

BS2

Variant has not been reported in patient or clinically-evaluated control populations.

BP7

Not applicable for frameshift variants

BP5

Relevant to dominant hearing loss disorders only.

BP3

Not applicable for frameshift variants

BP1

Not applicable for frameshift variants

BP4

Not applicable for frameshift variants

BP2

Variant has not been reported in patient or clinically-evaluated control populations.

PS1

Not applicable for frameshift variants

PS3

Variant has not been evaluated experimentally.

PS2

Variant has not been reported in patient or clinically-evaluated control populations.

PS4

Variant has not been reported in patient or clinically-evaluated control populations.

BA1

Highest MAF is 0.00088% (1/113352) in gnomAD v.2.1.1

PM4

Not applicable for frameshift variants

PM5

Not applicable for frameshift variants

PM1

PM1 not applicable for USH2A

PM3

One proband with autosomal recessive retinitis pigmentosa was identified to be carrying the p.Ile1183fs variant with no variant reported in trans (PMID: 35266249)

PM6

Variant has not been reported in patient or clinically-evaluated control populations.

PP2

Not applicable for frameshift variants

PP3

Not applicable for frameshift variants

PP1

Variant has not been reported in patient or clinically-evaluated control populations.

PP4

Variant has not been reported in patient populations.

Curation History

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