ClinVar Miner

Submissions for variant NM_002382.5(MAX):c.223C>T (p.Arg75Ter)

gnomAD frequency: 0.00001  dbSNP: rs387906650
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129940 SCV000184759 pathogenic Hereditary cancer-predisposing syndrome 2018-12-24 criteria provided, single submitter clinical testing The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 4 of the MAX gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation was originally identified in a family with multiple cases of early-onset bilateral pheochromocytomas (PCC); the PCC tumor of the proband demonstrated absent immunohistochemical staining and loss of heterozygosity for MAX (Comino-Méndez I et al. Nat. Genet., 2011 Jun;43:663-7). This pathogenic variant was also described in other individuals with bilateral PCC (Burnichon N et al. Clin. Cancer Res., 2012 May;18:2828-37; Pczkowska M et al. Clin. Endocrinol. (Oxf), 2013 Dec;79:817-23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV000524813 SCV000637870 pathogenic Hereditary pheochromocytoma-paraganglioma 2022-11-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29786). This premature translational stop signal has been observed in individual(s) with bilateral adrenal pheochromoytoma and adrenal pheochromocytoma (PMID: 21685915, 22452945, 23551045). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387906650, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg75*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438).
GeneDx RCV004700269 SCV005201973 pathogenic not provided 2023-07-26 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.196C>T p.R66X; This variant is associated with the following publications: (PMID: 25525159, Parisien-La Salle[2022]Abstract, 28152038, 30877234, 31666924, 29625052, 23551045, 21685915, 22452945, 34135865)
OMIM RCV000022653 SCV000043942 risk factor Pheochromocytoma, susceptibility to 2011-06-19 no assertion criteria provided literature only

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