Submissions for variant NM_000551.4(VHL):c.445G>T (p.Ala149Ser)

dbSNP: rs587780077

Total submissions: 5

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854559	SCV002238447	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2020-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with serine at codon 149 of the VHL protein (p.Ala149Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (PMID: 9435426, 23673869). It has also been observed to segregate with disease in related individuals. This variant is also known as c.658G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 127829). This variant is not present in population databases (ExAC no frequency).
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