Submissions for variant NM_001039141.3(TRIOBP):c.6556G>A (p.Gly2186Ser)

gnomAD frequency: 0.00031  dbSNP: rs191901426

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217336	SCV000270951	likely benign	not specified	2015-06-23	criteria provided, single submitter	clinical testing	p.Gly2186Ser in exon 19 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 6 mammals (mouse, rat, tenrec, opossum, Tasmanian devil, and wallaby) ha ve a serine (Ser) at this position despite high nearby amino acid conservation. This variant has been identified in 0.1% (11/13630) of South Asian chromosomes a nd 0.06% (35/54590) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191901426).
GeneDx	RCV000827584	SCV000969237	likely benign	not provided	2021-09-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000827584	SCV001040189	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217336	SCV002598675	uncertain significance	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: TRIOBP c.6556G>A (p.Gly2186Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 246352 control chromosomes in the gnomAD database, including 1 homozygote. c.6556G>A has been reported in the literature in an individual affected with Nonsyndromic Hearing Loss (Shearer_2013). This report does not provide unequivocal conclusions about association of the variant with Autosomal Recessive Nonsyndromic Hearing Loss 28. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000827584	SCV004147871	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	TRIOBP: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000827584	SCV005206441	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000827584	SCV001549720	likely benign	not provided		no assertion criteria provided	clinical testing	The TRIOBP p.Gly2186Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs191901426), ClinVar (classified as likely benign‚Äã by Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine and GeneDx) and LOVD 3.0 (classified as likely benign). The variant was also identified in control databases in 114 of 277736 chromosomes (1 homozygous) at a frequency of 0.00041 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: Other in 6 of 7084 chromosomes (freq: 0.000847), South Asian in 22 of 30178 chromosomes (freq: 0.000729), European (non-Finnish) in 70 of 127052 chromosomes (freq: 0.000551), African in 8 of 23882 chromosomes (freq: 0.000335), Latino in 7 of 35074 chromosomes (freq: 0.0002) and Ashkenazi Jewish in 1 of 10298 chromosomes (freq: 0.000097), while the variant was not observed in the East Asian and European (Finnish) populations. 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. The p.Gly2186 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. 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.