ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.445G>T (p.Ala149Ser) (rs587780077)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115746 SCV000149655 pathogenic not provided 2013-10-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted VHL c.445G>T at the cDNA level, p.Ala149Ser (A149S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant, previously called VHL 658G>T, has been reported in two large kindreds. Atuk et. al (1998) studied an American family with over 25 cases of Von Hippel-Lindau (VHL) disease type 2A in whom the mutation demonstrated complete segregation in the 10 affected and informative unaffected individuals who were tested. In addition, Mete et al. (2013) identified the mutation in a large Turkish kindred with VHL Type 2B. Although the mutation showed incomplete segregation - present in all 11 affected family members but also in 7 unaffected family members - all but one of the unaffected carriers were in the youngest generation and possibly not old enough to show signs of disease. In sum, the family studies support pathogenicity of this variant.VHL Ala149Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution of a neutral non-polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is located in the CCT binding domain. Multiple in silico algorithms predict that this mutation may be damaging to protein structure and function. Based on the currently available information, we consider VHL Ala149Ser to be a pathogenic variant.
Ambry Genetics RCV000492260 SCV000580954 pathogenic Hereditary cancer-predisposing syndrome 2015-09-20 criteria provided, single submitter clinical testing The p.A149S pathogenic mutation (also known as c.445G>T), located in coding exon 2 of the VHL gene, results from a G to T substitution at nucleotide position 445. The alanine at codon 149 is replaced by serine, an amino acid with similar properties. In one study, this alteration displayed good segregation with disease in a total of 7 individuals from a large family with 25 cases of clinically confirmed von Hippel-Lindau disease (VHLD) type 2A. In this family, symptoms of pheochromocytoma developed on average at 12.5 years, and definitive diagnoses occurred on average at 19.9 years. Of note, this alteration is referred to as c.658G>T in this paper (Atuk NO, et al. J. Clin. Endocrinol. Metab. 1998;83(1):117-20). This mutation was found in another large Turkish family with VHLD type 2B and displayed good segregation with disease in a total of 9 individuals from this kindred (Mete T, et al. Endocrine 2014;45(1):128-35). In addition, one in vitro functional study showed that the half life of the protein created by this variant was much shorter, 0.6 hours, when compared to that of wild type protein, 3.8 hours. In addition, this alteration displayed decreased physical interaction with two chaperonin proteins when compared to wild type interactions, suggesting potential abnormalities in chaperonin binding possibly contributing to rapid degradation (Yang C, et al. Cell Rep 2013;3(1):52-9). Based on the supporting evidence, p.A149S is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208783 SCV000697515 pathogenic Von Hippel-Lindau syndrome 2019-01-03 criteria provided, single submitter clinical testing Variant summary: VHL c.445G>T (p.Ala149Ser) results in a conservative amino acid change located in the alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246270 control chromosomes (gnomAD). c.445G>T has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Mete_2014, Atuk_1998). These data indicate that the variant is very likely to be associated with disease. Functional studies also show that the variant of interest impairs wild-type function (Yang_2013). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208783 SCV000264741 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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