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_206933.2(USH2A):c.4714C>T (p.Leu1572Phe)

CA143497

48521 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: cb930024-7594-4d61-95e2-e3c66fb53267

HGVS expressions

NM_206933.2:c.4714C>T
NM_206933.2(USH2A):c.4714C>T (p.Leu1572Phe)
NC_000001.11:g.216097127G>A
CM000663.2:g.216097127G>A
NC_000001.10:g.216270469G>A
CM000663.1:g.216270469G>A
NC_000001.9:g.214337092G>A
NG_009497.1:g.331270C>T
NM_206933.3:c.4714C>T
ENST00000307340.7:c.4714C>T

Likely Benign

Met criteria codes 2
BS1_Supporting BP2
Not Met criteria codes 2
BS2 PM3

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The p.Leu1572Phe variant in USH2A gene has a filtering allele frequency= 0.12% in Latino in gnomAD (54/35388 with 95% CI) which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1 supporting). It was reported in multiple publications as a polymorphism or as non-pathogenic based on detection among normal control chromosomes or other evidence (PMID: 18273898, 19881469 and 17085681). Although the variant was reported in trans with c.2299delG in one patient diagnosed with Usher syndrome type II and in another with unclassified Usher syndrome (PMID: 25097241 and 28944237), it was also identified in cis with c.2299delG; p.Glu767Serfs and in unknown configuration with c.2299delG and a stop codon (PMID: 25472526), both in patients with Usher syndrome type II (BP2; PMID: 20507924, 25097241, 17405132 and 26969326). Computational prediction using REVEL was 0.65 which did not meet the Hearing Loss Expert Panel (HL EP) specified threshold of >0.7 for PP3. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive Usher syndrome, type 2A based on the HL EP-specified ACMG/AMP criteria applied (BS1, BP2).
Met criteria codes
BS1_Supporting
filtering AF=0.12% Latino in gnomAD (54/35388 with 95% CI)
BP2
observed in cis with c.2299delG.
In 5 patients: in cis with c.2299delG + another het variant. In one patient: in cis with homozygous c.2299delG PubMed:26969326
seen in trans with c.2299delG in a patient with Usher syndrome type II PubMed:25097241
It was found with a high frequency among USH2 patients but was not found among the patients with non-syndromic RP. It was determined that most patients with the Leu1572Phe change also had the common USH2 mutation c.2299delG; Glu767fs, and Leu1572Phe is thus likely over-represented in the USH2 group due to linkage disequilibrium with that mutation. PubMed:20507924
11/50 USH2 Aalleles, and always in cis with (c.2299delG;p.Glu767fs). PubMed:17405132
observed in trans with one patient with Usher syndrome. No segregation was done but in direct communication with author he mentioned: If phasing by segregation analyses was not possible, compound-heterozygosity could only be assumed based on mutation types, previous descriptions PubMed:28944237
Not Met criteria codes
BS2
According to the paper it was reported as non-pathogenic (the paper reports their evidence as: Primarily this was based on the fact that they were detected among normal control chromosomes) PubMed:18273898
PM3
observed in trans with c.2299delG in 2 reports
In 5 patients: in cis with c.2299delG + another het variant. In one patient: in cis with homozygous c.2299delG PubMed:26969326
seen in trans with c.2299delG in a patient with Usher syndrome type II PubMed:25097241
It was found with a high frequency among USH2 patients but was not found among the patients with non-syndromic RP. It was determined that most patients with the Leu1572Phe change also had the common USH2 mutation c.2299delG; Glu767fs, and Leu1572Phe is thus likely over-represented in the USH2 group due to linkage disequilibrium with that mutation. PubMed:20507924
11/50 USH2 Aalleles, and always in cis with (c.2299delG;p.Glu767fs). PubMed:17405132
observed in trans with one patient with Usher syndrome. No segregation was done but in direct communication with author he mentioned: If phasing by segregation analyses was not possible, compound-heterozygosity could only be assumed based on mutation types, previous descriptions PubMed:28944237
Approved on: 2019-07-28
Published on: 2019-08-16
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