Submissions for variant NM_004782.4(SNAP29):c.354dup (p.Leu119fs)

dbSNP: rs751575036

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000280604	SCV000329589	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25356970, 31748968, 31589614, 33977139)
Illumina Laboratory Services, Illumina	RCV000778648	SCV000914980	uncertain significance	CEDNIK syndrome	2018-11-08	criteria provided, single submitter	clinical testing	The SNAP29 c.354dupG (p.Leu119AlafsTer15) variant results in a frameshift and is predicted to cause a premature truncation of the protein. The p.Leu119AlafsTer15 variant has been reported in one study, in which it is found in a homozygous state in an individual with an undiagnosed disorder (Farwell et al. 2015). This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
New York Genome Center	RCV000778648	SCV001480323	likely pathogenic	CEDNIK syndrome	2019-09-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000280604	SCV002072155	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000280604	SCV002233143	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu119Alafs*15) in the SNAP29 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SNAP29 are known to be pathogenic (PMID: 15968592, 21073448). This variant is present in population databases (rs751575036, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Pelizaeus-Merzbacher-like disease (PMID: 31748968). ClinVar contains an entry for this variant (Variation ID: 279932). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002519036	SCV003680581	pathogenic	Inborn genetic diseases	2022-05-25	criteria provided, single submitter	clinical testing	The c.354dupG (p.L119Afs*15) alteration, located in exon 2 (coding exon 2) of the SNAP29 gene, consists of a duplication of G at position 354, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected in the homozygous state, and in conjunction with another SNAP29 alteration, in multiple individuals with clinical features of CEDNIK syndrome (Farwell, 2015; Llaci, 2019; Mah-Som, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN)	RCV000454232	SCV000538078	pathogenic	Hypomyelinating leukodystrophy 2	2017-02-06	no assertion criteria provided	clinical testing
OMIM	RCV000778648	SCV002520479	pathogenic	CEDNIK syndrome	2022-05-23	no assertion criteria provided	literature only