Submissions for variant NM_000359.3(TGM1):c.61A>G (p.Thr21Ala)

gnomAD frequency: 0.00149  dbSNP: rs140542428

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000893471	SCV001037406	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110687	SCV001268154	uncertain significance	Autosomal recessive congenital ichthyosis 1	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.
Ambry Genetics	RCV002539413	SCV003732967	uncertain significance	Inborn genetic diseases	2021-07-09	criteria provided, single submitter	clinical testing	The c.61A>G (p.T21A) alteration is located in exon 2 (coding exon 1) of the TGM1 gene. This alteration results from a A to G substitution at nucleotide position 61, causing the threonine (T) at amino acid position 21 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003920795	SCV004733772	likely benign	TGM1-related condition	2022-06-07	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).
Natera, Inc.	RCV001110687	SCV001460576	likely benign	Autosomal recessive congenital ichthyosis 1	2019-11-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000893471	SCV001548844	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TGM1 p.Thr21Ala variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs140542428) and in control databases in 385 of 281634 chromosomes (0 homozygous) at a frequency of 0.001367 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 295 of 128088 chromosomes (freq: 0.002303), Ashkenazi Jewish in 11 of 10340 chromosomes (freq: 0.001064), Latino in 37 of 35422 chromosomes (freq: 0.001045), Other in 5 of 7214 chromosomes (freq: 0.000693), African in 14 of 24914 chromosomes (freq: 0.000562), European (Finnish) in 12 of 25108 chromosomes (freq: 0.000478), South Asian in 10 of 30616 chromosomes (freq: 0.000327), and East Asian in 1 of 19932 chromosomes (freq: 0.00005). The p.Thr21 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. This variant is classified as a variant of uncertain significance.