Variant: NM_000260.4(MYO7A):c.6560G>A (p.Gly2187Asp)

CA278713

43335 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 8815458c-46db-44af-b7e7-82344035be79

Approved on: 2022-08-03

Published on: 2022-08-03

HGVS expressions

NM_000260.4:c.6560G>A
NM_000260.4(MYO7A):c.6560G>A
NM_000260.4(MYO7A):c.6560G>A (p.Gly2187Asp)
NC_000011.10:g.77214608G>A
CM000673.2:g.77214608G>A
NC_000011.9:g.76925653G>A
CM000673.1:g.76925653G>A
NC_000011.8:g.76603301G>A
NG_009086.1:g.91344G>A
NG_009086.2:g.91363G>A
ENST00000409709.9:c.6560G>A
ENST00000670577.1:c.4361G>A
ENST00000409619.6:c.6413G>A
ENST00000409709.7:c.6560G>A
ENST00000458169.2:c.3986G>A
ENST00000458637.6:c.6440G>A
ENST00000481328.7:n.5110G>A
ENST00000605744.1:n.2074G>A
NM_000260.3:c.6560G>A
NM_001127180.1:c.6440G>A
NM_001127180.2:c.6440G>A
NM_001369365.1:c.6413G>A

Likely Pathogenic

• Met criteria codes: PP3 PP4 PM2_Supporting PM3

• Not Met criteria codes: BA1 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PS1 PS2 PS3 PS4 PP1 PP2 PM1 PM5 PM4 PM6 PVS1

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.6560G>A variant in MYO7A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 2187. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001190 (1/84018 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.915, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A (PP3). At least one patient with this variant displayed profound congenital deafness and retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10930322). This variant has been detected in at least two individuals with Usher syndrome. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant published by multiple submitters in ClinVar (c.2904G>T (p.Glu968Asp) and c.3719G>A (p.R1240Q)) and both of those were presumed in trans (1 PM3 point, PMID:10930322, LMM) (PM3). In summary, this variant was reviewed by the ClinGen Hearing Loss VCEP and classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.915, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A (PP3).
• PP4: At least one patient with this variant displayed profound congenital deafness and retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10930322).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001190 (1/84018 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PM3: This variant has been detected in at least two individuals with Usher syndrome. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant published by multiple submitters in ClinVar (c.2904G>T (p.Glu968Asp) and c.3719G>A (p.R1240Q)) and both of those were presumed in trans (1 PM3 point, PMID:10930322, LMM) (PM3).

Not Met criteria codes

• BA1: 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
• BS1: 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
• BP4: 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
• PS1: 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
• PS3: Disrupts interaction with the PDZ3 domain of USH1C. However, the experiment does not have great controls and this type of assay is not listed as adequate for PS3_Supporting
• PS4: 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
• PP2: 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
• PM4: 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
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline