Variant: NM_206933.4(USH2A):c.13396C>T (p.Pro4466Ser)

CA143316

48417 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: afedcdf5-4814-4f0e-a431-fb76cffe27e8

Approved on: 2022-11-22

Published on: 2023-02-06

HGVS expressions

NM_206933.4:c.13396C>T
NM_206933.4(USH2A):c.13396C>T (p.Pro4466Ser)
NC_000001.11:g.215674515G>A
CM000663.2:g.215674515G>A
NC_000001.10:g.215847857G>A
CM000663.1:g.215847857G>A
NC_000001.9:g.213914480G>A
NG_009497.1:g.753882C>T
NG_009497.2:g.753934C>T
ENST00000307340.8:c.13396C>T
ENST00000674083.1:c.13396C>T
ENST00000307340.7:c.13396C>T
NM_206933.2:c.13396C>T
NM_206933.3:c.13396C>T

Uncertain Significance

• Met criteria codes: BP4 PM3_Supporting

• Not Met criteria codes: BA1 BP2 BP3 BP1 BP5 BP7 BS2 BS3 BS4 BS1 PVS1 PP4 PP1 PP3 PP2 PS2 PS4 PS3 PS1 PM1 PM4 PM5 PM6 PM2

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 variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022)

Met criteria codes

• BP4: REVEL = 0.049 (<0.15)
• PM3_Supporting: This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: 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: 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria.
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: 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
• PS2: 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
• 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
• 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: 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: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria.