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]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_206933.2(USH2A):c.15433G>A (p.Val5145Ile)

CA143401

48464 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 42b06ec9-1249-4155-a6ab-a61c363e6c5f

HGVS expressions

NM_206933.2:c.15433G>A
NM_206933.2(USH2A):c.15433G>A (p.Val5145Ile)
NC_000001.11:g.215628900C>T
CM000663.2:g.215628900C>T
NC_000001.10:g.215802242C>T
CM000663.1:g.215802242C>T
NC_000001.9:g.213868865C>T
NG_009497.1:g.799497G>A
NM_206933.3:c.15433G>A
ENST00000307340.7:c.15433G>A

Benign

Met criteria codes 2
BP4 BA1
Not Met criteria codes 21
BS2 BS1 BS4 BP3 BP2 BP7 BP5 PS1 PS3 PS2 PS4 PVS1 PP3 PP1 PP4 PM2 PM6 PM5 PM4 PM1 PM3

Evidence Links 7

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The p.Val5145Ile variant in USH2A has been identified in at least 5 individuals with Usher syndrome; however, in 3 individuals no variant on the second allele was identified and in two individuals, no information about the other allele was provided (PMIDs 28041643, 25999674, 20829743, 27353947, 23591405). Additionally, the p.Val5145Ile variant was identified in 2 alleles of 56 retinitis pigmentosa patients, however it is unclear in which one or two patients these alleles were found (PMID 20591486). The filtering allele frequency of the p.Val5145Ile variant in the USH2A gene is 0.7% for European (Finnish) chromosomes by gnomAD (201/25124 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4) .In summary, this variant meets criteria to be classified as benign based primarily on population frequency data and the absence of cases with biallelic variants. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4.
Met criteria codes
BP4
REVEL prediction score of 0.126 meets the BP4 cut-off of <0.15
BA1
The p.Val5154Ile variant is present in 201/25124 European (Finnish) alleles in gnomAD (0.7% with a 95% confidence interval).
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The p.Val5154Ile variant is present in 201/25124 European (Finnish) alleles in gnomAD (0.7% with a 95% confidence interval).
BS4
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
BP2
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
BP5
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
PS3
Reports that computational tools predict the p.Val5145Ile variant is benign/tolerated. PubMed:20507924
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
2x2 Contingency table done with Yates' correlation: 201/25124 versus 6/1085. Not statistically significant.
In a group of 250 patients with RP, the p.Val5145Ile variant was found in one individual. PubMed:25999674
p.Val5145Ile variant was reported in one European female with RP. Identified by WGS. Not clear if the variant is homozygous or heterozygous. PubMed:28041643
Variant detected in 2 alleles of 56 RP patients. It is not clear if these alleles are in the same individual. PubMed:20591486
Variant present in heterozygosity in case #224 with sporadic Usher syndrome. This proband is also noted to carry a homozygous CDH23 p.V1620M variant that is benign in ClinVar, as well a a heterozygous DFNB31 p.S387W variant that is of unknown pathogenicity. Case not being counted. PubMed:23591405
Variant found in heterozygosity in an individual with Leber congenital amaurosis, but deemed benign along with a het. variant in the following genes: VPS13B, RPGRIP1, BBS10 and MKS1. PubMed:27353947
Patient #2 with fundus albipunctatus carried the p.Val5145Ile variant in het., as well as an NR2E3 het. variant and an RPI het. variant. This patient has a null homozygous variant in another gene identified as causative. PubMed:20829743
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL prediction score of 0.126 meets the BP4 cut-off of <0.15
PP1
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
PM2
The p.Val5154Ile variant is present in 201/25124 European (Finnish) alleles in gnomAD (0.7% with a 95% confidence interval).
PM6
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
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2019-01-14
Published on: 2019-10-18
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.