Submissions for variant NM_000551.4(VHL):c.21C>A (p.Asn7Lys)

gnomAD frequency: 0.00001  dbSNP: rs1060503561

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462197	SCV000553402	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-09-03	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 411973). This variant has not been reported in the literature in individuals affected with VHL-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 7 of the VHL protein (p.Asn7Lys).
Ambry Genetics	RCV000574549	SCV000675812	likely benign	Hereditary cancer-predisposing syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001356021	SCV004022820	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with clinical features of VHL who had a second pathogenic VHL variant, but phase could not be determined (Peri et al., 2016); This variant is associated with the following publications: (PMID: 27682873)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356021	SCV001551072	uncertain significance	not provided		no assertion criteria provided	clinical testing	The VHL p.N7K variant was identified in 1 of 12 proband chromosomes (frequency: 0.0833) from individuals with von Hippel-Lindau disease and was not identified in 12 control chromosomes from healthy individuals (Peri_2017_ PMID: 27682873). The variant was identified in dbSNP (ID: rs1060503561) and ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 1 of 137860 chromosomes at a frequency of 0.000007254 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the European (non-Finnish) population in 1 of 49770 chromosomes (freq: 0.00002), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.N7 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.