Submissions for variant NM_001079866.2(BCS1L):c.871C>T (p.Arg291Ter)

gnomAD frequency: 0.00005  dbSNP: rs201454788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195977	SCV000251195	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Nonsense 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 significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in mitochondrial dysfunction with reduced electron transport chain activity (Hinson et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 29704315, 25914718, 17314340)
Illumina Laboratory Services, Illumina	RCV000368540	SCV000427447	uncertain significance	BCS1L-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	The BCS1L c.871C>T (p.Arg291Ter) variant is a stop-gained variant. The p.Arg291Ter variant has been reported in one study in which it is found in a compound heterozygous state with a missense variant in one individual with Bjornstad syndrome (Hinson et al. 2007). The p.Arg291Ter variant was absent from 300 control chromosomes and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional complementation studies in yeast showed that the variant failed to support growth on media that require respiratory-chain metabolism (Hinson et al. 2007). The amount of superoxide produced by complex III activity was reduced by 61% in mitochondria in individuals with Bjornstad syndrome while complex I-dependent production of reactive oxygen species was increased by 30%. Due to the potential impact of stop-gained variants and the supporting evidence, this 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586158	SCV000698305	likely pathogenic	Pili torti-deafness syndrome	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: BCS1L c.871C>T (p.Arg291X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 250748 control chromosomes (gnomAD). c.871C>T has been reported in the literature in a compound heterozygote individual affected with Bjornstad syndrome (Hinson_2007). The authors of this study also reported experimental evidence evaluating an impact on protein function, demonstrating in a yeast complementation assay that the mutant protein failed to rescue growth on a medium that requires an active respiratory-chain. They also showed decreased electron-transport activities with increased production of reactive oxygen species in lymphocytes acquired from patients with Bjornstad syndrome and complex III deficiency (however, no patient specific data were provided, Hinson_2007). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl	RCV000675151	SCV000800755	likely pathogenic	GRACILE syndrome	2017-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000675151	SCV001162936	pathogenic	GRACILE syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV000195977	SCV001231785	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg291*) 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 (rs201454788, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Bjornstad syndrome (PMID: 17314340). ClinVar contains an entry for this variant (Variation ID: 214162). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000586158	SCV002503731	pathogenic	Pili torti-deafness syndrome	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 291 in exon 7 (of 9) of BCS1L, p.(Arg291*). It is expected to result in an absent or disrupted protein product in a gene where loss of function is an established mechanism of disease. The variant is present in a large population cohort at a frequency of 0.003%, which is consistent with a recessive condition (rs201454788, 8/282,138 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a second allele in a case diagnosed with Bjornstad syndrome (PMID: 17314340). Additionally, the variant demonstrates attenuated growth in a yeast complementation assay (PMID: 17314340). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC . Following criteria are met: PVS1, PM2, PS3_Supporting.
Baylor Genetics	RCV000586158	SCV004210781	pathogenic	Pili torti-deafness syndrome	2023-10-06	criteria provided, single submitter	clinical testing