Submissions for variant NM_000533.5(PLP1):c.712_713insTGCAGTTCCAAATG (p.His238fs)

dbSNP: rs1602385672

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001009119	SCV001168930	likely pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 40 amino acids are replaced with 25 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068469	SCV001233582	pathogenic	Hereditary spastic paraplegia 2	2023-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PLP1 protein in which other variant(s) (p.Gly246Ala) have been determined to be pathogenic (PMID: 15712223, 19825935). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 817891). This variant has not been reported in the literature in individuals affected with PLP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His238Leufs*26) in the PLP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the PLP1 protein.