Submissions for variant NM_001374504.1(TMPRSS6):c.457C>T (p.Arg153Cys)

gnomAD frequency: 0.00162  dbSNP: rs116092750

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989688	SCV004807198	uncertain significance	Iron-refractory iron deficiency anemia	2024-03-26	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001356407	SCV005194452	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV001356407	SCV005410260	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing	BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001356407	SCV005776917	likely benign	not provided	2024-08-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356407	SCV001551567	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TMPRSS6 p.Arg153Cys variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs116092750) and in control databases in 148 of 282736 chromosomes at a frequency of 0.0005235 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: African in 139 of 24946 chromosomes (freq: 0.005572), Latino in 4 of 35438 chromosomes (freq: 0.000113) and European (non-Finnish) in 5 of 129086 chromosomes (freq: 0.000039), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Arg153 residue is not 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004756221	SCV005345521	likely benign	TMPRSS6-related disorder	2024-05-10	no assertion criteria provided	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).