Submissions for variant NM_003784.4(SERPINB7):c.796C>T (p.Arg266Ter)

gnomAD frequency: 0.00019  dbSNP: rs142859678

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479535	SCV000567359	pathogenic	not provided	2022-08-11	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost, and other loss-of-function variants have been reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 24514002, 27786350, 27663160, 27569382, 27543371, 27506501, 28211129, 29888704, 30256384, 30581033, 30833958, 30004585, 32406097, 31980526, 24077912, 34426522, 33362511, 32892407, 33914963, 34379845, 27666198, 24207119, 24773080)
Fulgent Genetics, Fulgent Genetics	RCV000088682	SCV000894164	pathogenic	Palmoplantar keratoderma, Nagashima type	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479535	SCV001247832	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000088682	SCV002020073	pathogenic	Palmoplantar keratoderma, Nagashima type	2021-03-14	criteria provided, single submitter	clinical testing
3billion	RCV000088682	SCV002058138	pathogenic	Palmoplantar keratoderma, Nagashima type	2023-12-27	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.053%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000102446 /PMID: 24207119 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000088682	SCV002761696	pathogenic	Palmoplantar keratoderma, Nagashima type	2021-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479535	SCV003283223	pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg266*) in the SERPINB7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the SERPINB7 protein. This variant is present in population databases (rs142859678, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Nagashima-type palmoplantar keratoderma (NPPK) (PMID: 24207119, 24514002, 27543371, 27666198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese and Han Chinese ancestry (PMID: 24514002, 24773080). ClinVar contains an entry for this variant (Variation ID: 102446). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415873	SCV004108780	pathogenic	SERPINB7-related disorder	2023-03-08	criteria provided, single submitter	clinical testing	The SERPINB7 c.796C>T variant is predicted to result in premature protein termination (p.Arg266*). This variant has been reported to be causative for autosomal recessive Nagashima-type palmoplantar keratosis and has been described as a founder mutation in Asian populations (Kubo et al. 2013. PubMed ID: 24207119; Yin et al. 2014. PubMed ID: 24514002; Zhang et al. 2016. PubMed ID: 27666198). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-61471522-C-T). Nonsense variants in SERPINB7 are expected to be pathogenic. This variant is interpreted as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000088682	SCV004812579	pathogenic	Palmoplantar keratoderma, Nagashima type	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change in SERPINB7 is a nonsense variant predicted to cause a premature stop codon, p.(Arg266*), that is predicted to escape nonsense-mediated decay and remove <10% of the protein (removes amino acids 226-380) in a gene where loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.8% (347/44,860 alleles) in the East Asian population, which is higher than expected for a recessive disease. However, this variant is an East Asian founder mutation for Nagashima-type palmoplantar keratoderma. It has been reported in multiple affected individuals in the homozygous and compound heterozygous state (with at least one individual with a pathogenic variant on the second allele) and segregates with disease in at least one family (PMID: 24207119, 35178744). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PVS1_Strong, PP1, BS1.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000088682	SCV005417605	pathogenic	Palmoplantar keratoderma, Nagashima type		criteria provided, single submitter	clinical testing	PM3_VeryStrong+PVS1_Strong
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000088682	SCV005914891	pathogenic	Palmoplantar keratoderma, Nagashima type	2023-03-24	criteria provided, single submitter	research
OMIM	RCV000088682	SCV000121604	pathogenic	Palmoplantar keratoderma, Nagashima type	2014-10-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000088682	SCV001142482	pathogenic	Palmoplantar keratoderma, Nagashima type	2020-01-06	no assertion criteria provided	curation	NM_003784.3:c.796C>T in the SERPINB7 gene has an allele frequency of 0.007 Asia in East Asian subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Palmoplantar keratoderma, nagashima type, compound heterozygous with c.218_219del2ins12, c.455-1G>A, respectively (PMID: 24207119). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong; PP4.