Submissions for variant NM_206933.4(USH2A):c.13217T>C (p.Leu4406Pro)

gnomAD frequency: 0.00009  dbSNP: rs745693690

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171541	SCV001334326	uncertain significance	Usher syndrome	2024-11-20	reviewed by expert panel	curation	The c.13217T>C variant in USH2A is a missense variant predicted to cause substitution of leucine by proline at amino acid 4406 (p.Leu4406Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.02% (15/74934) in the African / African American population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.338, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been identified in one individual with Usher syndrome who was compound heterozygous with a pathogenic variant phase unknown (PP4, 0.5 point PM3; PMID: 36011402). This individual also had a third variant that was reviewed by the Hearing Loss VCEP and was determined to be likely benign. This variant was also identified in an individual with retinitis pigmentosa who was compound heterozygous with a pathogenic variant, though phase was unknown (0.5 point PM3, PMID: 37217489). The variant was also reported in other individuals with Usher syndrome; however, these individuals were not awarded any evidence as zygosity / phasing was unknown, the second variant was likely benign, or the individual had a possible alternate explanation for disease (PMID: 26927203, 24944099, 36011402). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024).
Counsyl	RCV000672328	SCV000797425	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-01-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000986516	SCV001135531	uncertain significance	Usher syndrome type 2A	2023-04-21	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074933	SCV001240540	uncertain significance	Retinal dystrophy	2017-05-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366541	SCV001562847	pathogenic	not provided	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4406 of the USH2A protein (p.Leu4406Pro). This variant is present in population databases (rs745693690, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 24944099, 26927203; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556334). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001374884	SCV001572164	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.13217T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx	RCV001366541	SCV001787971	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24944099, 37217489, 36011402)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282318	SCV002571069	uncertain significance	not specified	2022-07-29	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.13217T>C (p.Leu4406Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250910 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13217T>C has been reported in cohorts of Usher patients without strong evidence for causality (examples: Baux_2014 and Pierrache_2016). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Six submitters including ClinGen Hearing Loss Variant Curation Expert Panel classified this variant VUS. Two submitters classified the variant as likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Human Genetics, Universidade de São Paulo	RCV001171541	SCV005324770	uncertain significance	Usher syndrome	2024-05-01	criteria provided, single submitter	research	The USH2A:NM_206933.2:c.13217T>C has extremely low frequency in gnomAD population databases, it is associated with a recessive disorder, detected in trans with a pathogenic variant, in affected cases (PM3). Here it was found with c.12100G>T in one affected individual with Usher syndrome, with three additional untested siblings, born from unaffected unrelated couple.
Natera, Inc.	RCV000986516	SCV002088272	uncertain significance	Usher syndrome type 2A	2021-01-28	no assertion criteria provided	clinical testing