ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.968G>A (p.Arg323Gln)

gnomAD frequency: 0.00003  dbSNP: rs121918717
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520296 SCV000617732 pathogenic not provided 2021-10-07 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: marked reduction in enzyme activity (Candi et al., 1998; Herman et al., 2009); This variant is associated with the following publications: (PMID: 7824952, 9545389, 19241467, 31168818, 32105361, 31046801, 9593710, 23278109)
Invitae RCV000520296 SCV000955335 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 323 of the TGM1 protein (p.Arg323Gln). This variant is present in population databases (rs121918717, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 7824952, 9545389, 19241467, 23278109). It has also been observed to segregate with disease in related individuals. This variant is also known as 322Q. ClinVar contains an entry for this variant (Variation ID: 12484). 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 expected to disrupt TGM1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 9261103, 9593710). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000013303 SCV001554489 pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281702 SCV002570584 pathogenic Lamellar ichthyosis 2022-07-07 criteria provided, single submitter clinical testing Variant summary: TGM1 c.968G>A (p.Arg323Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (4.1e-05 vs 0.0021), allowing no conclusion about variant significance. c.968G>A has been reported in the literature in at least one homozygous and multiple compound heterozygous individuals affected with Lamellar Ichthyosis, including cases of self-improving collodion ichthyosis (e.g.Huber_1995, Hennies_1998, Herman_2009, Simpson_2020, Diep_2020, Mohamad_2021). These data indicate that the variant is very likely to be associated with disease. Experimental studies examining the activity of the variant protein in vitro have found reduced cytosolic activity and markedly reduced (2-26% of normal) membrane-bound activity, indicating that the variant has a negative impact on protein function (Huber_1997, Candi_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000013303 SCV002763729 pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000013303 SCV002810868 pathogenic Autosomal recessive congenital ichthyosis 1 2021-07-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000013303 SCV003828029 pathogenic Autosomal recessive congenital ichthyosis 1 2022-06-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000013303 SCV004203739 pathogenic Autosomal recessive congenital ichthyosis 1 2023-10-14 criteria provided, single submitter clinical testing
OMIM RCV000013303 SCV000033550 pathogenic Autosomal recessive congenital ichthyosis 1 1995-01-27 no assertion criteria provided literature only
Counsyl RCV000013303 SCV000793786 likely pathogenic Autosomal recessive congenital ichthyosis 1 2017-08-30 no assertion criteria provided clinical testing
Natera, Inc. RCV000013303 SCV001459980 pathogenic Autosomal recessive congenital ichthyosis 1 2020-09-16 no assertion criteria provided clinical testing

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