Submissions for variant NM_001079866.2(BCS1L):c.232A>G (p.Ser78Gly)

gnomAD frequency: 0.00042  dbSNP: rs28937590

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000006542	SCV000236535	pathogenic	GRACILE syndrome	2014-09-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000519547	SCV000617082	pathogenic	not provided	2022-12-09	criteria provided, single submitter	clinical testing	Functional studies demonstrate that S78G is associated with decreased stability of the BCS1L protein (Visapaa et al., 2002); Transgenic mice with homozygosity for the S78G variant demonstrate decreased BCS1L expression and decreased Rieske iron-sulfur protein incorporation into complex III (Davoudi et al., 2014); This variant is associated with the following publications: (PMID: 21274865, 27997587, 29782205, 28424480, 30530468, 22829922, 18386115, 31980526, 12547234, 27809283, 32637629, 34662929, 24466228, 12215968)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000006542	SCV000680154	pathogenic	GRACILE syndrome	2017-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006542	SCV000698304	pathogenic	GRACILE syndrome	2016-07-14	criteria provided, single submitter	clinical testing	Variant summary: The BCS1L c.232A>G (p.Ser78Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 48/122498 control chromosomes at a frequency of 0.0003918, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCS1L variant (0.0004725). Homozygotes of this variant have been reported exclusively in Finnish patients with GRACILE syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476936	SCV000893576	pathogenic	Pili torti-deafness syndrome; GRACILE syndrome; Mitochondrial complex III deficiency nuclear type 1	2022-03-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006542	SCV001162935	pathogenic	GRACILE syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000006542	SCV001193863	pathogenic	GRACILE syndrome	2019-12-09	criteria provided, single submitter	clinical testing	NM_004328.4(BCS1L):c.232A>G(S78G) is classified as pathogenic in the context of BCS1L-related disorders. Sources cited for classification include the following: PMID 12215968 and 21274865. Classification of NM_004328.4(BCS1L):c.232A>G(S78G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000519547	SCV001207152	pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 78 of the BCS1L protein (p.Ser78Gly). This variant is present in population databases (rs28937590, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with clinical features of BCS1L-related conditions (PMID: 12215968, 12547234, 18386115, 19508421). It is commonly reported in individuals of Finnish ancestry (PMID: 12215968). ClinVar contains an entry for this variant (Variation ID: 6167). 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: 12215968, 21274865). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000519547	SCV002064003	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003472987	SCV004210777	pathogenic	Pili torti-deafness syndrome	2023-10-23	criteria provided, single submitter	clinical testing
OMIM	RCV000006542	SCV000026725	pathogenic	GRACILE syndrome	2002-10-01	no assertion criteria provided	literature only
Counsyl	RCV000983982	SCV000678004	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2015-07-21	no assertion criteria provided	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000519547	SCV000778193	pathogenic	not provided	2016-03-08	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000006542	SCV002076346	pathogenic	GRACILE syndrome	2021-01-19	no assertion criteria provided	clinical testing