Submissions for variant NM_206933.4(USH2A):c.14219C>A (p.Ala4740Asp)

gnomAD frequency: 0.00006  dbSNP: rs539192853

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252667	SCV001428426	pathogenic	Usher syndrome	2024-06-28	reviewed by expert panel	curation	The c.14219C>A (p.Ala4740Asp) variant in USH2A is a missense variant predicted to cause a substitution of alanine by aspartic acid at amino acid 4740. The highest population minor allele frequency in gnomAD v4.0.0 is 0.006102% (72/1180006) in the European (Non-Finish) 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 0.309, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least 2 individuals with Usher syndrome, and in at least 5 individuals with Retinitis Pigmentosa (RP) (4 PM3 pts). The two individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Arg737*, p.Ser1849fs; PMIDs: 33576794, 38465142). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4, PMID: 33576794). Of the individuals with RP, four individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Ser1849fs, p.Arg737*, c.7595-2144A>G, p.Arg4192Cys; PMIDs: 30718709, 34781295, 32531858). One individual was compound heterozygous and confirmed in trans by parental testing for the variant and a pathogenic or likely pathogenic variant (p.Arg1653*; PMIDs: 34781295) (PM3_VeryStrong). Patients with this variant may present with either autosomal recessive (AR) Usher syndrome or with AR isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3_VeryStrong, PP4; Version 2; 4/17/24).
GeneDx	RCV000492984	SCV000581721	likely pathogenic	not provided	2023-09-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23591405, 28559085, 33576794, 22952768, 30718709, 25649381, 32531858, 32037395, 34781295, 36284670)
CeGaT Center for Human Genetics Tuebingen	RCV000492984	SCV000780322	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	USH2A: PM2, PM3, PP4, BP4
Blueprint Genetics	RCV001073605	SCV001239156	pathogenic	Retinal dystrophy	2019-07-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000492984	SCV001418529	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 4740 of the USH2A protein (p.Ala4740Asp). This variant is present in population databases (rs539192853, gnomAD 0.008%). This missense change has been observed in individual(s) with Usher syndrome or retinal disease (PMID: 22952768, 25649381, 28559085, 30718709; 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: 429215). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000787725	SCV001950396	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Ala4740Asp variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PP1, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002226464	SCV002505564	uncertain significance	Retinal dystrophy; Retinal degeneration	2022-03-22	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM3, PM2_SUP, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003126756	SCV003802704	likely pathogenic	Retinitis pigmentosa 39	2023-02-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003126756	SCV004207686	likely pathogenic	Retinitis pigmentosa 39	2024-03-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073605	SCV005068834	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005018826	SCV005645704	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-03-14	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787725	SCV000926725	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research