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 Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Strong segregation with disease (lod >3 = >10 meioses)
Integrated Genetics/Laboratory Corporation of America 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.
Division of Genomic Diagnostics,The 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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