Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Liping Wei Laboratory, |
RCV000754671 | SCV000804763 | likely pathogenic | Autism spectrum disorder | 2018-08-01 | criteria provided, single submitter | research | |
| New York Genome Center | RCV003448336 | SCV004176183 | uncertain significance | Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability | 2023-05-11 | criteria provided, single submitter | clinical testing | The inherited c.803+1G>A splice-site variant identified in the HEPACAM has been reported in the literature as heterozygous in an individual with development delay (walked independently at age 15 months, spoke first word at age 41 months and can only say less than 5 words) and mental retardation [PMID:30763456]. It has also been deposited in ClinVar [ClinVar ID: 562146] as Likely Pathogenic (1 submission). The c.803+1G>A variant is observed in 34 out of~590,062 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8; Allele frequency in East Asiansubpopulation is ~0.12%). The c.803+1G>A variant is located in the canonical splice donor site in intron 4 of this 7-exon gene and is presumed to result in loss of nativesplice donor site, which might result in loss-of-function either through protein truncation or nonsense-mediated mRNA decay. Loss-of-function is not an established disease mechanism for autosomal dominant MLC2B. Given its relatively high occurrence in the population databases, lack of functional studies, and its inheritance from an apparently unaffected parent of this individual, the c.803+1G>A splice-site variant identified in the HEPACAM gene is classified as a Variant of Uncertain Significance for autosomal dominant MLC2B. |