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]

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

CA278713

43335 (ClinVar)

Gene: MYO7A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
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:n.4361G>A
ENST00000409619.6:c.6413G>A
ENST00000409709.7:c.6560G>A
ENST00000458169.2:n.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
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Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM2_Supporting PM3 PP4 PP3
Not Met criteria codes 22
PM1 PM4 PM5 BA1 PM6 BS2 PVS1 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS4 PS3 PS1 PP1 PP2

Evidence Links 2

Expert Panel

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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).
Found presumed in trans with p.Glu968Asp (a two star pathogenic variant in clinvar). 0.5 points. PubMed:10930322
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).
All patients had profound congenital deafness and RP PubMed:10930322
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).
Not Met criteria codes
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
BA1
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
BS2
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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 PubMed:28439001
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
Found presumed in trans with p.Glu968Asp (a two star pathogenic variant in clinvar). 0.5 points. PubMed:10930322
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
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
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
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
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 PubMed:28439001
PS1
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
Curation History
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