Submissions for variant NM_001080476.3(GRXCR1):c.331T>C (p.Tyr111His)

gnomAD frequency: 0.00016  dbSNP: rs201002003

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000382382	SCV000449557	uncertain significance	Autosomal recessive nonsyndromic hearing loss 25	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000604378	SCV000711071	uncertain significance	not specified	2017-06-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Tyr111His var iant in GRXCR1 has not been previously reported in individuals with hearing loss . It has been identified in 27/125910 European chromosomes by the genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs201002003); ho wever this frequency is not high enough to rule out a pathogenic role. The varia nt has also been reported in ClinVar (Variation ID: 348818). The Tyrosine (Tyr) at position 111 is conserved through mammals, but is not highly conserved in evo lutionary distant species with >30 species carry a Histidine (His) at this posit ion, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools suggest the variant may not impact the protein. In summary, while the clinical significance of the p.Tyr111His variant is uncertain, these data suggest that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000735068	SCV000863260	uncertain significance	not provided	2018-09-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000735068	SCV002027860	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000735068	SCV003450657	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 111 of the GRXCR1 protein (p.Tyr111His). This variant is present in population databases (rs201002003, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GRXCR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 348818). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.