Submissions for variant NM_017671.5(FERMT1):c.676dup (p.Gln226fs)

dbSNP: rs748240859

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481477	SCV000567497	pathogenic	not provided	2024-01-05	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; This variant is associated with the following publications: (PMID: 22466645, 34008892, 14962093, 33921969, 30838128, 22220914)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000789034	SCV000928373	pathogenic	Kindler syndrome	2018-07-10	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4, PP5
3billion, Medical Genetics	RCV000789034	SCV002058846	pathogenic	Kindler syndrome	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000419593, PMID:14962093).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000035, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481477	SCV003443361	pathogenic	not provided	2024-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln226Profs*17) in the FERMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FERMT1 are known to be pathogenic (PMID: 14962093, 21936020). This variant is present in population databases (rs748240859, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Kindler syndrome (PMID: 14962093, 30838128). ClinVar contains an entry for this variant (Variation ID: 419593). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000789034	SCV002072441	not provided	Kindler syndrome		no assertion provided	literature only	Common pathogenic variant
PreventionGenetics, part of Exact Sciences	RCV004755927	SCV005366880	pathogenic	FERMT1-related disorder	2024-06-04	no assertion criteria provided	clinical testing	The FERMT1 c.676dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln226Profs*17). This variant has been reported in the homozygous state to be causative for Kindler syndrome in multiple individuals (Ashton et al. 2004. PubMed ID: 14962093; Gkaitatzi et al. 2019. PubMed ID: 30838128). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. We interpret this variant as pathogenic.