Submissions for variant NM_033305.3(VPS13A):c.9431_9432del (p.Glu3144fs)

dbSNP: rs1085307750

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489660	SCV000577210	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 31 amino acids are replaced with 5 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12404112, 30713887, 31543803, 24077912)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000489660	SCV001401240	pathogenic	not provided	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu3144Valfs*6) in the VPS13A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the VPS13A protein. This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Chorea-acanthocytosis (PMID: 12404112, 30713887, 31543803). It has also been observed to segregate with disease in related individuals. This variant is also known as 9431_9432delAG (p.3134Rfsx5). ClinVar contains an entry for this variant (Variation ID: 426695). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003133278	SCV003816543	likely pathogenic	Chorea-acanthocytosis	2022-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003133278	SCV005725662	pathogenic	Chorea-acanthocytosis	2024-11-26	criteria provided, single submitter	clinical testing	Variant summary: VPS13A c.9431_9432delAG (p.Glu3144ValfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 250700 control chromosomes. c.9431_9432delAG has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Choreoacanthocytosis or with clinical features strongly suggestive of the disease (e.g. Dobson-Stone_2002, Richard_2019, Murphy_2018, Merwick_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12404112, 31543803, 30622839, 30713887). ClinVar contains an entry for this variant (Variation ID: 426695). Based on the evidence outlined above, the variant was classified as pathogenic.