Submissions for variant NM_021175.4(HAMP):c.223C>T (p.Arg75Ter)

gnomAD frequency: 0.00003  dbSNP: rs200488037

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002051236	SCV002116334	likely pathogenic	Hereditary hemochromatosis	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg75*) in the HAMP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the HAMP protein. This variant is present in population databases (rs200488037, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with hemochromatosis (PMID: 22297252, 33016646). ClinVar contains an entry for this variant (Variation ID: 1350113). This variant disrupts a region of the HAMP protein in which other variant(s) (p.Cys78Tyr) have been observed in individuals with HAMP-related conditions (PMID: 15099344). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226497	SCV003923160	likely pathogenic	Hemochromatosis type 2B	2023-03-22	criteria provided, single submitter	clinical testing	Variant summary: HAMP c.223C>T (p.Arg75X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. No truncations downstream of this variant have been reported in ClinVar or HGMD. The variant allele was found at a frequency of 2e-05 in 251484 control chromosomes. c.223C>T has been reported in the literature in individuals affected with Hemochromatosis Type 2B in homozygous (Hattori_2012a) and compound heterozygous individuals carrying a second likely pathogenic allele (Wu_2020). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.