Submissions for variant NM_001377299.1(NDUFS2):c.1138C>G (p.His380Asp)

gnomAD frequency: 0.00055  dbSNP: rs144411579

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725777	SCV000251877	uncertain significance	not provided	2021-04-05	criteria provided, single submitter	clinical testing	Identified in the single heterozygous state without a second NDUFS2 variant in an individual with a FARSB-related disorder in the published literature, and suggested to be unrelated to the individual's phenotype (Antonellis et al., 2018); 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: 29573043)
Eurofins Ntd Llc (ga)	RCV000725777	SCV000339314	uncertain significance	not provided	2016-02-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725777	SCV000891862	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	NDUFS2: PP3, BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001527	SCV001158839	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 6	2019-02-21	criteria provided, single submitter	clinical testing	The NDUFS2 c.1138C>G; p.His380Asp variant (rs144411579), is reported in the literature in a large sequencing study (Bastarache 2018), but has not been reported to be associated with disease. This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 214795), and is found in the non-Finnish European population with an overall allele frequency of 0.09% (108/123,964 alleles) in the Genome Aggregation Database. The histidine at codon 380 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.His380Asp variant is uncertain at this time. References: Bastarache L et al. Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science. 2018 Mar 16;359(6381):1233-1239.
Illumina Laboratory Services, Illumina	RCV001100725	SCV001257257	uncertain significance	Mitochondrial complex I deficiency, nuclear type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000725777	SCV002129590	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 380 of the NDUFS2 protein (p.His380Asp). This variant is present in population databases (rs144411579, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NDUFS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
MGZ Medical Genetics Center	RCV001001527	SCV002581129	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 6	2022-08-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515415	SCV003572426	uncertain significance	Inborn genetic diseases	2021-08-04	criteria provided, single submitter	clinical testing	The c.1138C>G (p.H380D) alteration is located in exon 12 (coding exon 11) of the NDUFS2 gene. This alteration results from a C to G substitution at nucleotide position 1138, causing the histidine (H) at amino acid position 380 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.