ClinVar Miner

Submissions for variant NM_001374504.1(TMPRSS6):c.631G>T (p.Gly211Cys)

dbSNP: rs2146149841
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001944716 SCV002128067 uncertain significance not provided 2021-10-11 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with iron-refractory iron deficiency anemia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 220 of the TMPRSS6 protein (p.Gly220Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV004556088 SCV005045267 uncertain significance Iron-refractory iron deficiency anemia 2024-05-22 criteria provided, single submitter curation The heterozygous p.Gly211Cys variant in TMPRSS6 was identified by our study, in the compound heterozygous state, along with a pathogenic variant, in one individual with iron-refractory iron deficiency anemia. The variant has not been previously reported in individuals withiron-refractory iron deficiency anemia, and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 1366522) and has been interpreted as uncertain significance by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly211Cys variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PM2_Supporting, PP3 (Richards 2015).

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