Submissions for variant NM_173477.5(USH1G):c.1258C>G (p.Leu420Val)

gnomAD frequency: 0.00080  dbSNP: rs139897506

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041414	SCV000065109	uncertain significance	not specified	2016-07-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Leu420Val var iant in USH1G has now been identified in 2 individuals with Usher syndrome and 5 individuals with hearing loss. One of the individuals with Usher syndrome had t wo pathogenic variants in another gene which explained the disease (Glockle 2014 ). A variant affecting the remaining copy of USH1G was not detected in any of th e other individuals (LMM data). This variant has been identified in 0.2% (109/62 876) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs139897506). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. Computational prediction tools and conservation analyses do not provi de strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Leu420Val variant is uncertain, these data sugge st that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000724716	SCV000227576	uncertain significance	not provided	2015-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724716	SCV001219451	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 420 of the USH1G protein (p.Leu420Val). This variant is present in population databases (rs139897506, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with USH1G-related conditions. ClinVar contains an entry for this variant (Variation ID: 48126). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH1G protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001123313	SCV001282137	uncertain significance	Usher syndrome type 1G	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000724716	SCV001448951	uncertain significance	not provided	2019-07-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000724716	SCV001780078	likely benign	not provided	2020-05-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23591405, 26878454)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724716	SCV001550759	uncertain significance	not provided		no assertion criteria provided	clinical testing	The USH1G p.Leu420Val variant was identified as a heterozygous variant in 1 of 340 proband chromosomes (frequency: 0.00294) from an individual with Usher syndrome, however two pathogenic variants in the USH2A gene (p.C3090*, p.W3702*) were identified in this individual and were presumed to be the cause of disease (Glockle_2014_PMID:23591405). The variant was identified in dbSNP (ID: rs139897506), ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and EGL Genetic Diagnostics), and LOVD 3.0 (conflicting classifications). The variant was identified in control databases in 258 of 280002 chromosomes (1 homozygous) at a frequency of 0.0009214 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 215 of 127098 chromosomes (freq: 0.001692), Other in 5 of 7168 chromosomes (freq: 0.000698), European (Finnish) in 14 of 25108 chromosomes (freq: 0.000558), African in 10 of 24562 chromosomes (freq: 0.000407), Latino in 10 of 35374 chromosomes (freq: 0.000283) and South Asian in 4 of 30562 chromosomes (freq: 0.000131), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724716	SCV001958732	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724716	SCV001971939	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541211	SCV004762020	likely benign	USH1G-related disorder	2022-07-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814970	SCV005071356	uncertain significance	Retinal dystrophy	2022-01-01	no assertion criteria provided	clinical testing