Submissions for variant NM_005006.7(NDUFS1):c.683T>C (p.Val228Ala)

gnomAD frequency: 0.00012  dbSNP: rs370411488

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493658	SCV000582622	likely pathogenic	not provided	2024-03-03	criteria provided, single submitter	clinical testing	Reported previously in unrelated individuals with isolated complex I deficiency who each harbored a second NDUFS1 variant (PMID: 21458341, 31557978, 37273706, 19167255); Fibroblasts from two patients harboring the V228A variant and another NDUFS1 variant exhibited significantly reduced NDUFS1 protein levels compared to control cell lines (PMID: 21458341); 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: 31589614, 27126960, 36074903, 36042640, 36462614, 31557978, 20382551, 21458341, 37273706, 36183138, 19167255)
Illumina Laboratory Services, Illumina	RCV000779296	SCV000915878	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 5	2017-09-11	criteria provided, single submitter	clinical testing	The NDUFS1 c.683T>C (p.Val228Ala) variant has been reported in four studies and identified in four compound heterozygotes with complex I deficiency (Pagniez-Mammeri et al. 2009; Hoefs et al. 2010; Danhauser et al. 2011). The three individuals identified by Hoefs et al. (2010) and Danhauser et al. (2011) expired before age four. The variant was absent from 100 healthy controls but is reported at a frequency of 0.000349 in European American population of the Exome Sequencing Project. Analysis of cultured skin fibroblasts from patients found that the enzyme activity of complex I was significantly decreased (Hoefs et al. 2010; Danhauser et al. 2011). Danhauser et al. (2011) also transduced and expressed the variant in a construct with wild type protein and the complex I activity doubled in both individuals with the p.Val228Ala variant. Based on the evidence, the p.Val228Ala variant is classified as pathogenic for NDUFS1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000493658	SCV002822785	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	NDUFS1: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PP3
Baylor Genetics	RCV000779296	SCV004040738	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 5	2023-12-13	criteria provided, single submitter	clinical testing