Submissions for variant NM_018965.4(TREM2):c.97C>T (p.Gln33Ter)

gnomAD frequency: 0.00002  dbSNP: rs104894002

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000721927	SCV001146845	pathogenic	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2	2019-10-17	criteria provided, single submitter	curation	This variant is interpreted as Pathogenic for Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 , autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PM3, PS3, PVS1-Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512810	SCV003439332	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 5219). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TREM2 function (PMID: 25615530). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with autosomal recessive TREM2-related conditions (PMID: 12754369, 23318515). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Gln33*) in the TREM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TREM2 are known to be pathogenic (PMID: 12080485, 12754369, 12883936, 12925681, 23318515, 23582655). This variant is present in population databases (rs104894002, gnomAD 0.006%).
Ambry Genetics	RCV004018565	SCV004970658	pathogenic	Inborn genetic diseases	2022-05-03	criteria provided, single submitter	clinical testing	The c.97C>T (p.Q33*) alteration, located in exon 2 (coding exon 2) of the TREM2 gene, consists of a C to T substitution at nucleotide position 97. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 33. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/248072) total alleles studied. The highest observed frequency was 0.005% (5/110958) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state in multiple unrelated individuals with TREM2-related polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. It has also been found to cosegregate among affected homozygous siblings (Coomans, 2018; Guerreiro, 2013; Bock, 2013; Soragna, 2003). Based on the available evidence, this alteration is classified as pathogenic.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV005089179	SCV005849055	pathogenic	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly	2025-02-10	criteria provided, single submitter	research	The highest population allele frequency in gnomAD V4.0 is 0.00008003 (0.008%; 5/62478 in Remaining population). There are no homozygous observations. PM1_Met: variant occurs in exon 2 (highly conserved IgV domain) together with other pathogenic variants (PMID:36813542). PM3 Met: max 1 point awarded for homozygous observations of variant in probands with consistent phenotype for disorder. PP1 Met: 1 informative meiosis in 1 family (PMID: 12754369). PS3_Supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID:25615530). PS4_Supporting: Homozygous observations of variant in 2 probands with consistent phenotype for disorder (PMID: 29142083, 23318515). PVS1_Strong: null variant (nonsense or frameshift variant) predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease (PMID: 12080485, 12754369). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
OMIM	RCV000721927	SCV000025711	pathogenic	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2	2005-05-10	no assertion criteria provided	literature only
GeneReviews	RCV000005529	SCV000223801	not provided	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1		no assertion provided	literature only	This variant has been reported to cause a PLOSL with typical bone pathology on radiologic examination but also a frontotemporal dementia-like syndrome without bone pathology on radiographs.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000005529	SCV000734498	pathogenic	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000005529	SCV000745890	pathogenic	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1	2016-03-14	no assertion criteria provided	clinical testing