Submissions for variant NM_152722.5(HEPACAM):c.265G>A (p.Gly89Ser)

dbSNP: rs387907053

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000390259	SCV000329992	pathogenic	not provided	2023-09-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein function (Arnedo et al., 2014; Hoegg-Beiler et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31960914, 24647135, 20301707, 27535533, 21419380, 25044933)
Invitae	RCV000390259	SCV002240335	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HEPACAM function (PMID: 25044933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 30919). This missense change has been observed in individual(s) with autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts (PMID: 21419380). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 89 of the HEPACAM protein (p.Gly89Ser).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000023907	SCV002820285	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability		criteria provided, single submitter	clinical testing	The missense variant p.G89S in HEPACAM (NM_152722.5) has been previously reported as a de novo mutation in autosomal dominant megalencephalic leukoencephalopathy (Lopez-Hernandez T et al). Studies in HeLa cells demonstrate that G89S impacts the function of the HEPACAM protein (Arnedo et al, 2014). The variant has been submitted to ClinVar as Pathogenic. The p.G89S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools are contradictory in their predictions (SIFT-Tolerated, Polyphen-2-damaging) and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407358	SCV004115068	pathogenic	HEPACAM-related condition	2022-12-13	criteria provided, single submitter	clinical testing	The HEPACAM c.265G>A variant is predicted to result in the amino acid substitution p.Gly89Ser. This variant has been reported in individuals with autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts, and functional studies support its pathogenicity (López-Hernández et al. 2011. PubMed ID: 21419380; Arnedo et al. 2014. PubMed ID: 25044933; Elorza-Vidal et al 2020. PubMed ID: 31960914). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000023907	SCV000045198	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability	2011-04-08	no assertion criteria provided	literature only
GeneReviews	RCV000055996	SCV000087051	not provided	Megalencephalic leukoencephalopathy with subcortical cysts 2A		no assertion provided	literature only