Submissions for variant NM_001079866.2(BCS1L):c.205C>T (p.Arg69Cys)

gnomAD frequency: 0.00011  dbSNP: rs377025174

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197059	SCV000251193	likely pathogenic	not provided	2024-12-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19508421, 17403714, 17314340, 12215968, 11528392, 31435670, 34662929, 27959697)
Ambry Genetics	RCV000623904	SCV000740812	likely pathogenic	Inborn genetic diseases	2015-03-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197059	SCV001205466	pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 69 of the BCS1L protein (p.Arg69Cys). This variant is present in population databases (rs377025174, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of mitochondrial complex III deficiency (PMID: 27959697, 31435670; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214160). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BCS1L protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BCS1L function (PMID: 31435670). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000415034	SCV002518569	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000675122	SCV002583278	likely pathogenic	GRACILE syndrome		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000415034	SCV002768359	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bjornstad syndrome (MIM#262000), GRACILE syndrome (MIM#603358) and mitochondrial complex III deficiency, nuclear type (MIM#1124000). Missense variants have been reported to cause all conditions, with clinical severity dependant on the quantity and location of production of reactive oxygen species (PMID: 17314340). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated import auxiliary sequence (PMID: 31435670). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more commonly and recently as likely pathogenic. It has been reported in several compound heterozygous individuals with Leigh syndrome or aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties (ClinVar, LOVD, PMID: 31435670, PMID: 30634555). An additional individual with mitochondrial complex III deficiency has also been reported, but this individual had an additional hemizygous variant in the NLGN4X gene, which is considered part of a dual molecular diagnosis (PMID: 27959697, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis of this variant using the muscle biopsy of an affected individual and yeast complementation assays, has demonstrated that this variant has a partial loss of function effect on protein activity.Additionally, it reduced protein expression, mitochondrial respiratory activity and complex III activity (PMID: 31435670). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000675122	SCV003922924	pathogenic	GRACILE syndrome	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: BCS1L c.205C>T (p.Arg69Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR014851) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251480 control chromosomes (gnomAD). This frequency is not higher than the estimated maximal expected for a pathogenic variant in BCS1L causing GRACILE Syndrome (0.00047), allowing no conclusion about variant significance. c.205C>T has been reported in the literature in multiple compound heterozygous individuals affected with symptoms that belong to the spectrum of BCS1L-related disorders (Olahova_2019, Hikmat_2021, Jou_2019, Posey_2017), all carrying a (likely) pathogenic variant in trans. These data indicate that the variant is likely to be associated with disease. At least one of these publications also reported experimental evidence, and demonstrated a partial loss of function in patient derived cells and in yeast complementation assays (Olahova_2019). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=3) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474948	SCV004210796	likely pathogenic	Pili torti-deafness syndrome	2024-02-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001810436	SCV005650493	likely pathogenic	Pili torti-deafness syndrome; GRACILE syndrome; Mitochondrial complex III deficiency nuclear type 1	2024-02-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000415034	SCV000328852	uncertain significance	Mitochondrial complex III deficiency nuclear type 1	2016-05-01	flagged submission	clinical testing	Our laboratory reported dual molecular diagnoses in BCS1L (NM_004328.4:c.598C>T; NM_004328.4:c.205C>T ; in trans) and NLGN4X (NM_181332.1:c.301C>T) in an individual with short stature, failure to thrive, rickets, Fanconi syndrome, delayed motor milestones, absent speech, developmental regression, intellectual disability, hypotonia, seizure disorder, gait ataxia, abnormal movements (laughing behavior and tongue protrusion), dysmorphic features, microcephaly, history of seizure disorder.
Natera, Inc.	RCV000675122	SCV001455774	likely pathogenic	GRACILE syndrome	2020-09-16	no assertion criteria provided	clinical testing
Myriad Genetics, Inc.	RCV001810436	SCV002060338	uncertain significance	Pili torti-deafness syndrome; GRACILE syndrome; Mitochondrial complex III deficiency nuclear type 1	2021-11-01	flagged submission	clinical testing	NM_004328.4(BCS1L):c.205C>T(R69C) is a missense variant classified as a variant of uncertain significance in the context of BCS1L-related disorders. R69C has been observed in cases with relevant disease (PMID: 31435670, 30634555, 27959697). Functional assessments of this variant are available in the literature (PMID: 31435670). R69C has been observed in population frequency databases (gnomAD: FIN 0.03%). In summary, there is insufficient evidence to classify NM_004328.4(BCS1L):c.205C>T(R69C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.