Submissions for variant NM_015294.6(TRIM37):c.1919G>A (p.Arg640His)

gnomAD frequency: 0.00140  dbSNP: rs112762655

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000350888	SCV000331487	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000354466	SCV000404353	likely benign	Mulibrey nanism syndrome	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000350888	SCV001036470	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000350888	SCV001552612	likely benign	not provided		no assertion criteria provided	clinical testing	The TRIM37 p.Arg395His variant was not identified in the literature but was identified in dbSNP (ID: rs112762655), ClinVar (classified as a VUS by Illumina and EGL Genetics) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 491 of 282714 chromosomes (1 homozygous) at a frequency of 0.001737 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 420 of 129088 chromosomes (freq: 0.003254), European (Finnish) in 45 of 25120 chromosomes (freq: 0.001791), Other in 8 of 7216 chromosomes (freq: 0.001109), African in 10 of 24964 chromosomes (freq: 0.000401), Latino in 7 of 35404 chromosomes (freq: 0.000198) and Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), but was not observed in the East Asian or South Asian populations. The p.Arg395 residue is 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000350888	SCV001800212	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000350888	SCV001975584	uncertain significance	not provided		no assertion criteria provided	clinical testing