Submissions for variant NM_001079866.2(BCS1L):c.399del (p.Glu133fs)

dbSNP: rs751484879

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778594	SCV000914901	uncertain significance	BCS1L-related disorder	2017-08-22	criteria provided, single submitter	clinical testing	The BCS1L c.399delA (p.Glu133AspfsTer25) variant has been reported in one study and is found in one individual with complex III deficiency in a compound heterozygous state with a missense variant. The variant was also present in the unaffected mother in a heterozygous state (Tegelberg et al. 2017). Control data are unavailable for the p.Glu133AspfsTer25 variant, which is reported at a frequency of 0.00036 in the European American population of the Exome Sequencing Project. Based on the limited evidence, the p.Glu133AspfsTer25 variant is classified as a variant of unknown significance but suspicious for pathogenicity for BCS1L-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000801063	SCV000940819	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu133Aspfs*25) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs751484879, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BCS1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 631845). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000801063	SCV003821650	likely pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003472307	SCV004210799	pathogenic	Pili torti-deafness syndrome	2024-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001825516	SCV005039956	pathogenic	GRACILE syndrome	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: BCS1L c.399delA (p.Glu133AspfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.6e-05 in 251496 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BCS1L causing GRACILE Syndrome (7.6e-05 vs 0.00047), allowing no conclusion about variant significance. c.399delA has been reported in the literature in individuals affected with GRACILE Syndrome. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 631845). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001825516	SCV002076349	pathogenic	GRACILE syndrome	2020-12-15	no assertion criteria provided	clinical testing