Submissions for variant GRCh38/hg38 4q28.2(chr4:127964562-127965767)x0

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003327719	SCV004034167	uncertain significance	Neuronal ceroid lipofuscinosis 7	2023-08-24	criteria provided, single submitter	research	A homozygous deletion of exon 1 in MFSD8 (NM_001371596.2) was identified by exome sequencing in one individual with neuronal ceroid lipofuscinosis ([GRCh 38] chr4:127964562_127965767x0). These breakpoints have been estimated by exome sequencing only and therefore may not reflect the true breakpoints. Inheritance information is unavailable. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. This intragenic variant deletes the first coding exon and is predicted to cause loss of the methionine initiation codon. This alteration is then predicted to lead to a truncated or absent protein. There is potential for rescue from a downstream methionine initiation codon. Loss of function of MFSD8 is an established disease mechanism in autosomal recessive neuronal ceroid lipofuscinosis (https://search.clinicalgenome.org/kb/gene-dosage). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.45 points, A: 0 points, 4-5: 0.15 points; Total: 0.6 points; Riggs 2020 (PMID: 31690835).