Submissions for variant NM_147196.3(TMIE):c.191C>T (p.Ser64Leu)

gnomAD frequency: 0.00026  dbSNP: rs189895472

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152052	SCV000200659	uncertain significance	not specified	2016-09-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ser64Leu vari ant in TMIE has been previously reported in the heterozygous state in four indiv iduals with hearing loss; however, an alternate explanation of the hearing loss was identified in two of these individuals (Vona 2014, LMM data). This variant h as been identified across several populations by the Exome Aggregation Consortiu m with a frequency of 0.04% (46/120742) of the total chromosomes (ExAC, http://e xac.broadinstitute.org; dbSNP rs189895472). However, its frequency is not high e nough to rule out a pathogenic role. Computational prediction tools and conserva tion analyses do not provide strong support for or against an impact to the prot ein. In summary, while the clinical significance of the p.Ser64Leu variant is un certain, the identification of the variant in several individuals with an altern ate explanation of the hearing loss suggests it is more likely benign.
Eurofins Ntd Llc (ga)	RCV000724726	SCV000227557	uncertain significance	not provided	2017-03-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999882	SCV000884699	uncertain significance	Autosomal recessive nonsyndromic hearing loss 6	2019-03-18	criteria provided, single submitter	clinical testing	The TMIE c.191C>T; p.Ser64Leu variant (rs189895472) was detected in a patient with recessive hereditary hearing loss in the heterozygous state; however, a likely causative variant in another gene was also identified (Vona 2014). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.04% (identified on 105 out of 281,070 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 165460). The serine at position 64 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Ser64Leu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Ser64Leu variant cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV000999882	SCV001308244	uncertain significance	Autosomal recessive nonsyndromic hearing loss 6	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.
GeneDx	RCV000724726	SCV001830911	likely benign	not provided	2021-04-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24875298)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724726	SCV002247597	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 64 of the TMIE protein (p.Ser64Leu). This variant is present in population databases (rs189895472, gnomAD 0.06%). This missense change has been observed in individual(s) with deafness (PMID: 24875298). ClinVar contains an entry for this variant (Variation ID: 165460). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.