Submissions for variant NM_198994.3(TGM6):c.115A>T (p.Ser39Cys)

gnomAD frequency: 0.00036  dbSNP: rs144201778

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210538	SCV000262957	uncertain significance	Inborn genetic diseases	2012-11-16	criteria provided, single submitter	clinical testing	N/AN/ABased on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately 0.05% (5/10758) total alleles studied. The T-allele was observed in 0.07% (5/7020) European American alleles and was not observed among 3738 African American alleles studied (http://snp.gs.washington.edu/EVS). This amino acid position is poorly conserved in available vertebrate species.This alteration is predicted to be possibly damaging with a score of 0.950 (sensitivity: 0.79; specificity: 0.95)This alteration is predicted to be tolerated with a score of 0.190 (conservation: 1.88)
Athena Diagnostics Inc	RCV000993304	SCV001146157	benign	not provided	2019-02-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137367	SCV001297301	uncertain significance	Spinocerebellar ataxia type 35	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000993304	SCV002440048	benign	not provided	2024-01-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000993304	SCV004149764	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TGM6: BP4
PreventionGenetics, part of Exact Sciences	RCV003897460	SCV004722511	likely benign	TGM6-related condition	2020-06-15	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000993304	SCV001549615	likely benign	not provided		no assertion criteria provided	clinical testing	The TGM6 p.Ser39Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs144201778) and ClinVar (classified as uncertain significance by Ambry Genetics). The variant was identified in control databases in 120 of 281364 chromosomes (1 homozygous) at a frequency of 0.0004265 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: South Asian in 23 of 30534 chromosomes (freq: 0.000753), European (non-Finnish) in 93 of 128320 chromosomes (freq: 0.000725), Other in 1 of 7192 chromosomes (freq: 0.000139) and Latino in 3 of 35326 chromosomes (freq: 0.000085), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Ser39 residue is not 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.