Submissions for variant NM_000601.6(HGF):c.1891G>A (p.Val631Met)

gnomAD frequency: 0.00053  dbSNP: rs145494248

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155127	SCV000204813	uncertain significance	not specified	2018-04-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val631Met var iant in HGF has been previously reported by our laboratory in the heterozygous s tate in 3 individuals with hearing loss, none of whom has a second variant on th e other allele. This variant has been identified in 0.11% (132/125958) of Europe an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org/; dbSNP rs145494248). Although this variant has been seen in the gen eral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Val631Met variant is uncertain; however, we would lean towards a benign role based on population frequency. ACMG/AMP Criteria applied: BS1_Suppo rting.
GeneDx	RCV001719971	SCV000730670	likely benign	not provided	2021-05-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18564920)
Mendelics	RCV000987900	SCV001137393	benign	Autosomal recessive nonsyndromic hearing loss 39	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001719971	SCV002189930	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 631 of the HGF protein (p.Val631Met). This variant is present in population databases (rs145494248, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with HGF-related conditions (PMID: 18564920). ClinVar contains an entry for this variant (Variation ID: 178380). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001719971	SCV003917161	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	HGF: PP3