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]
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Variant: NM_000260.4(MYO7A):c.3527G>A (p.Ser1176Asn)

CA242907

196099 (ClinVar)

Gene: MYO7A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 981fcdec-991d-4878-a19d-3e45b688fc3b
Approved on: 2020-05-20
Published on: 2020-05-21

HGVS expressions

NM_000260.4:c.3527G>A
NM_000260.4(MYO7A):c.3527G>A (p.Ser1176Asn)
NM_000260.3:c.3527G>A
NM_001127180.1:c.3527G>A
NM_001127180.2:c.3527G>A
NM_001369365.1:c.3494G>A
ENST00000409619.6:c.3494G>A
ENST00000409709.7:c.3527G>A
ENST00000458169.2:n.1070G>A
ENST00000458637.6:c.3527G>A
ENST00000467137.1:n.54G>A
ENST00000481328.7:n.1070G>A
NC_000011.10:g.77189367G>A
CM000673.2:g.77189367G>A
NC_000011.9:g.76900412G>A
CM000673.1:g.76900412G>A
NC_000011.8:g.76578060G>A
NG_009086.1:g.66103G>A
NG_009086.2:g.66122G>A

Uncertain Significance

Met criteria codes 1
BP2
Not Met criteria codes 3
PP3 PM2 PM3

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.3527G>A (p.Ser1176Asn) variant in MYO7A was present in 0.057% (lower bound of the 95% CI of 33/42036) of African alleles in gnomAD v3 (BS1_Supporting not met). It has been observed in at least 3 individuals with Usher syndrome type 1. However, in one proband the p.Ser1176Asn variant was observed in cis with another pathogenic/likely pathogenic variant in MYO7A (BP2; PMID: 26969326). The remaining probands did not have other pathogenic or likely pathogenic variants in MYO7A identified (PM3 and PP4 not met; PMID: 27344577, 27460420, 31479088). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BP2.
Met criteria codes
BP2
Observed in cis with another pathogenic/likely pathogenic variant in MYO7A, which was in the homozygous state (PMID: 26969326).
PubMed:27344577
PubMed:26969326
PubMed:31479088
PubMed:27460420
Not Met criteria codes
PP3
REVEL score 0.638. Alamut does not predict an impact to splicing. Several animals (including 4 mammals) in the UCSC database have Cys at this site, but none have Asn.
PM2
Present in 0.06617% (16/24180) of African alleles in gnomAD v2.1.1. However, in v3, present in 0.07850% (33/42036) of African alleles.
PM3
Observed in at least 3 individuals with Usher syndrome type 1; however, these probands either had possible alternate mechanisms of disease or only carried another VUS with phase unknown (PMID: 27344577, 27460420, 31479088, 26969326).
PubMed:27344577
PubMed:26969326
PubMed:31479088
PubMed:27460420
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