Submissions for variant NM_001122955.4(BSCL2):c.974dup (p.Ile326fs)

dbSNP: rs749890533

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000412601	SCV000593785	pathogenic	Congenital generalized lipodystrophy type 2	2017-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387719	SCV001588415	pathogenic	Charcot-Marie-Tooth disease type 2	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile262Hisfs*12) in the BSCL2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BSCL2 are known to be pathogenic (PMID: 11479539, 23564749). This variant is present in population databases (rs749890533, gnomAD 0.08%). This premature translational stop signal has been observed in individuals with autosomal recessive BSCL2-related conditions (PMID: 27612026, 30903322, 31770241). This variant is also known as c.974dupG, c.975insG, and c.1126insG. ClinVar contains an entry for this variant (Variation ID: 372120). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV002473000	SCV002770484	pathogenic	not provided	2021-09-13	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002502439	SCV002793624	pathogenic	Congenital generalized lipodystrophy type 2; Hereditary spastic paraplegia 17; Severe neurodegenerative syndrome with lipodystrophy; Neuronopathy, distal hereditary motor, type 5C	2024-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701455	SCV005202303	pathogenic	BSCL2-related disorder	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: BSCL2 c.782dupG (p.Ile262HisfsX12) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.782dupG has been reported in the literature in individuals affected with BSCL2-Related Disorders (examples, Agarwal_2003, Opri_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 14557463, 27632409). ClinVar contains an entry for this variant (Variation ID: 372120). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796166	SCV005415796	pathogenic	Congenital generalized lipodystrophy type 2; Severe neurodegenerative syndrome with lipodystrophy		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_Strong+PP4
3billion	RCV005252873	SCV005904492	pathogenic	Severe neurodegenerative syndrome with lipodystrophy	2023-11-14	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: 0.006%). Predicted Consequence/Location: 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. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000372120 /PMID: 14557463). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneReviews	RCV000412601	SCV000490141	not provided	Congenital generalized lipodystrophy type 2		no assertion provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003311803	SCV004011993	uncertain significance	Berardinelli-Seip congenital lipodystrophy	2016-01-06	no assertion criteria provided	literature only