ClinVar Miner

Submissions for variant NM_007259.5(VPS45):c.712G>A (p.Glu238Lys)

gnomAD frequency: 0.00001  dbSNP: rs782269909
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000049321 SCV002290553 likely pathogenic Congenital neutropenia-myelofibrosis-nephromegaly syndrome 2023-02-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 238 of the VPS45 protein (p.Glu238Lys). This variant is present in population databases (rs782269909, gnomAD 0.009%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects VPS45 function (PMID: 23738510). 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 VPS45 protein function. ClinVar contains an entry for this variant (Variation ID: 55907). This missense change has been observed in individuals with VPS45 deficiency (PMID: 23738510, 26358756, 32037586).
3billion, Medical Genetics RCV000049321 SCV002572955 likely pathogenic Congenital neutropenia-myelofibrosis-nephromegaly syndrome 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.44). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with VPS45-related disorder (ClinVar ID: VCV000055907 / PMID: 26358756). A different missense change at the same codon (p.Glu238Gln) has been reported to be associated with VPS45-related disorder (PMID: 23738510). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV000049321 SCV005673398 likely pathogenic Congenital neutropenia-myelofibrosis-nephromegaly syndrome 2024-04-15 criteria provided, single submitter clinical testing
OMIM RCV000049321 SCV000081753 pathogenic Congenital neutropenia-myelofibrosis-nephromegaly syndrome 2013-07-04 no assertion criteria provided literature only

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