Submissions for variant NM_152722.5(HEPACAM):c.523A>T (p.Lys175Ter)

gnomAD frequency: 0.00001  dbSNP: rs752637604

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380252	SCV001578247	pathogenic	not provided	2018-06-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys175*) in the HEPACAM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752637604, ExAC 0.01%). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in HEPACAM are known to be pathogenic (PMID: 21419380, 24202401). This variant has not been reported in the literature in individuals with HEPACAM-related disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323873	SCV004029926	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: HEPACAM c.523A>T (p.Lys175X) 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 8e-06 in 250402 control chromosomes. To our knowledge, no occurrence of c.523A>T in individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 2b, Remitting, With Or Without Mental Retardation and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.