ClinVar Miner

Submissions for variant NM_213653.4(HJV):c.665T>A (p.Ile222Asn)

gnomAD frequency: 0.00003  dbSNP: rs74315325
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001065184 SCV001230133 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 222 of the HJV protein (p.Ile222Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs74315325, ExAC 0.001%). This missense change has been observed in individual(s) with juvenile hemochromatosis (PMID: 14647275). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2367). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689403 SCV005184442 uncertain significance not specified 2024-05-31 criteria provided, single submitter clinical testing Variant summary: HJV c.665T>A (p.Ile222Asn) results in a non-conservative amino acid change located in the N-terminal domain (IPR010536) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 282880 control chromosomes (gnomAD). c.665T>A has been reported in the literature in individuals affected with Hemochromatosis Type 2A (Papanikolaou_2003, Lee_2004, Pissia_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 14647275, 15194541, 14982867). ClinVar contains an entry for this variant (Variation ID: 2367). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000002464 SCV005672498 likely pathogenic Hemochromatosis type 2A 2024-06-10 criteria provided, single submitter clinical testing
OMIM RCV000002464 SCV000022622 pathogenic Hemochromatosis type 2A 2004-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000002464 SCV002094714 uncertain significance Hemochromatosis type 2A 2020-12-02 no assertion criteria provided clinical testing

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