ClinVar Miner

Submissions for variant NM_002150.3(HPD):c.1005C>G (p.Ile335Met)

gnomAD frequency: 0.00051  dbSNP: rs137852868
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000001642 SCV000376743 likely benign Tyrosinemia type III 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina RCV000386406 SCV000376744 likely benign Hawkinsinuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000953322 SCV001099887 benign Hawkinsinuria; Tyrosinemia type III 2024-01-31 criteria provided, single submitter clinical testing
Mendelics RCV000386406 SCV001138848 uncertain significance Hawkinsinuria 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001091863 SCV001248117 likely benign not provided 2023-08-01 criteria provided, single submitter clinical testing HPD: BS2
GeneDx RCV001091863 SCV001850174 likely benign not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10942115, 25219469, 17560158)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488319 SCV004241268 likely benign not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: HPD c.1005C>G (p.Ile335Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251474 control chromosomes, predominantly at a frequency of 0.0073 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in HPD causing Tyrosinemia Type 3 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1005C>G has been reported in the literature in individuals affected with Tyrosinemia Type 3 without strong evidence for causality (Ganapathy_2019, Ruetschi_2000). These report(s) do not provide unequivocal conclusions about association of the variant with Tyrosinemia Type 3. 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: 31069529, 10942115). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign/Likely benign, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000001642 SCV000021798 pathogenic Tyrosinemia type III 2000-06-01 no assertion criteria provided literature only

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