Submissions for variant NM_003172.4(SURF1):c.574C>T (p.Arg192Trp)

gnomAD frequency: 0.00004  dbSNP: rs782190413

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199387	SCV000252352	pathogenic	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 12515039, 24027061, 27896082, 19780766, 23829769, 16542579, 12943968, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631410	SCV000752482	pathogenic	Leigh syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 192 of the SURF1 protein (p.Arg192Trp). This variant is present in population databases (rs782190413, gnomAD 0.01%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease, type 4 (CMT4) or Leigh syndrome (PMID: 12515039, 19780766, 24027061, 27896082). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 215235). 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 SURF1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg192 amino acid residue in SURF1. Other variant(s) that disrupt this residue have been observed in individuals with SURF1-related conditions (PMID: 16542579, 23829769), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000199387	SCV002016822	likely pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492907	SCV002784998	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1; Charcot-Marie-Tooth disease type 4K	2021-10-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000631410	SCV003929318	pathogenic	Leigh syndrome	2023-04-13	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.574C>T (p.Arg192Trp) results in a non-conservative amino acid change in 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 1.2e-05 in 249494 control chromosomes (gnomAD). c.574C>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with Leigh Syndrome, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g Pecina_2003, Piekutowska-Abramczuk_2009, Echaniz-Laguna_2013, Wedatilake_2013, Shimbo_2014). These data indicate that the variant is likely to be associated with disease. Assessment of fibroblast mitochondria from a compound heterozygous patient with the variant (c.574C>T/c.841delCT) showed undetectable Surf1 protein levels and COX activity approximately 20% of normal (Pecina_2003). Additionally, another variant affecting the same amino acid, p.Arg192Gln, has been observed in affected individuals and classified as likely pathogenic by our laboratory, suggesting Arg192 may be important for protein function. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV003314575	SCV004014755	pathogenic	Mitochondrial disease	2023-02-16	criteria provided, single submitter	clinical testing	The SURF1 c.574C>T (p.Arg192Trp) missense variant results in the substitution of arginine at amino acid position 192 with tryptophan. This variant has been reported in at least five individuals with primary mitochondrial disease, in trans with another SURF1 variant (PMID: 19780766; PMID: 23829769; PMID: 24027061; PMID: 27896082). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000121 in the African/African-American population (version 2.1.1). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. This variant was identified in trans with a pathogenic variant. Based on the available evidence, the c.574C>T (p.Arg192Trp) variant is classified as pathogenic for primary mitochondrial disease.
OMIM	RCV000202523	SCV000257493	pathogenic	Charcot-Marie-Tooth disease type 4K	2013-10-22	no assertion criteria provided	literature only