Submissions for variant NM_152722.5(HEPACAM):c.1198G>A (p.Val400Met)

gnomAD frequency: 0.00024  dbSNP: rs770477104

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000512664	SCV000536518	uncertain significance	not provided	2018-10-02	criteria provided, single submitter	clinical testing	The V400M variant in the HEPACAM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. No data are available from ethnically-matched control populations to assess the frequency of this variant. The V400M variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V400M as a variant of uncertain significance, which may be related to the reported intellectual disability and autism spectrum disorder in this individual.
CeGaT Center for Human Genetics Tuebingen	RCV000512664	SCV000608626	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196308	SCV001366899	uncertain significance	Megalencephalic leukoencephalopathy with subcortical cysts 2A	2019-08-12	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000512664	SCV002132503	uncertain significance	not provided	2023-12-11	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 400 of the HEPACAM protein (p.Val400Met). This variant is present in population databases (rs770477104, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with HEPACAM-related conditions. ClinVar contains an entry for this variant (Variation ID: 393149). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Fulgent Genetics, Fulgent Genetics	RCV002502591	SCV002780460	uncertain significance	Megalencephalic leukoencephalopathy with subcortical cysts 1; Megalencephalic leukoencephalopathy with subcortical cysts 2A; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability	2021-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362787	SCV004055326	uncertain significance	Inborn genetic diseases	2023-08-24	criteria provided, single submitter	clinical testing	The c.1198G>A (p.V400M) alteration is located in exon 7 (coding exon 7) of the HEPACAM gene. This alteration results from a G to A substitution at nucleotide position 1198, causing the valine (V) at amino acid position 400 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV000512664	SCV005191539	uncertain significance	not provided		criteria provided, single submitter	not provided