Submissions for variant NM_173477.5(USH1G):c.310A>G (p.Met104Val)

gnomAD frequency: 0.00031  dbSNP: rs149529031

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152559	SCV000201792	uncertain significance	not specified	2013-09-29	criteria provided, single submitter	clinical testing	The Met104Val variant in USH1G has not been reported in individuals with hearing loss, but has been identified in 3/8600 (0.03%) European American chromosomes b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s149529031). Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. In summary, additional data is needed to determine the clinical significance of this variant.
Illumina Laboratory Services, Illumina	RCV000778515	SCV000914793	uncertain significance	USH1G-Related Disorders	2018-11-23	criteria provided, single submitter	clinical testing	The USH1G c.310A>G (p.Met104Val) variant has been reported in three studies in which it is identified in a total of four individuals. The p.Met104Val variant was reported in a compound heterozygous state with a frameshift variant in two siblings from a non-consanguineous Dutch family with early onset hearing loss, but no eye abnormalities or signs of retinitis pigmentosa (Oonk et al. 2015). The variant was also reported in a homozygous state in one individual with no specific phenotype details from a cohort of patients with prelingual, moderate to profound probable autosomal recessive non-syndromic hearing loss (Sommen et al. 2016), and in a heterozygous state in one individual with a retinal dystrophy phenotype who was also compound heterozygous for two variants in the ABCA4 gene (Tiwari et al. 2016). The variant was absent from 350 Dutch control subjects and is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Molecular modelling predicts that the p.Met104Val variant causes a change at the third ankyrin domain surface but does not alter the domain structure (Oonk et al. 2015). Based on the evidence, the p.Met104Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for USH1G-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001064558	SCV001229468	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 104 of the USH1G protein (p.Met104Val). This variant is present in population databases (rs149529031, gnomAD 0.03%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 25255398). ClinVar contains an entry for this variant (Variation ID: 166402). 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 not expected to disrupt USH1G protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects USH1G function (PMID: 31637240). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001064558	SCV001447700	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375211	SCV001571913	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Supporting, BP4_Supporting
GeneDx	RCV001064558	SCV002039023	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Identified in trans with a second variant in affected individuals in a family with nonsyndromic hearing loss (Maria Oonk et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive, suggesting that the variant may disrupt interactions with some proteins but that sufficient residual function may be retained (Sorusch et al., 2017; Sorusch et al., 2019); This variant is associated with the following publications: (PMID: 30245029, 28137943, 31637240, 27353947, 27068579, 25255398)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152559	SCV002104112	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: USH1G c.310A>G (p.Met104Val) results in a conservative amino acid change located in the ANK3 domain (Sorusch_2019) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251262 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH1G causing Usher Syndrome (0.00014 vs 0.0014), allowing no conclusion about variant significance. c.310A>G has been reported in the literature in compound heterozygosity with another variant in the USH1G gene (c.780insGCAC, p.Tyr261Alafs*96) in two Dutch siblings affected with non-syndromic hearing loss (NSHL) (example, Oonk_2015). It has also been reported as a VUS with a non-informative genotype (i.e., second allele not specified) in settings of multigene panel testing in cohorts of patients with NSHL (example, Sommen_2016), as a non-informative genotype in settings of exome sequencing of cohorts with Retinal dystrophies (example, Tiwari_2016), as a non-informative genotype in settings of multigene panel testing of cohorts with sporadic Menieres disease (MD) (example, Gallego-Martinez_2019). The Deafness Variation Database (DVB) cites this variant as pathogenic based on a custom-built internal computational pipeline (example, Azaiez_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of USH1G binding (residual activity at approximately 10-30% of wild-type) to intraflagellar transport (IFT) molecules in the primary cilia (example, Sorusch_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 27353947, 30828346, 25255398, 27068579, 31637240). ClinVar contains an entry for this variant (Variation ID: 166402). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.