Submissions for variant NM_003172.4(SURF1):c.813_818dup (p.His271_Leu272dup)

dbSNP: rs782488388

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196024	SCV000252356	likely pathogenic	not provided	2014-06-09	criteria provided, single submitter	clinical testing	c.813_818dupTCTGCA: p.His271_Leu272dup (H271_L272dup) in exon 8 of the SURF1 gene (NM_003172.2). The normal sequence with the bases that are duplicated in braces is AGCA{dupTCTGCA}GTAC. The c.813_818dupTCTGCA variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The c.813_818dupTCTGCA variant results in an in-frame duplication of two amino acids (Histidine 271 and Leucine 272) at a highly conserved residue in the SURF1 protein. Whether or not the duplication of two amino acids affects the function of the SURF1 protein is not known without functional studies. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae	RCV000820421	SCV000961132	uncertain significance	Leigh syndrome	2022-08-16	criteria provided, single submitter	clinical testing	This variant, c.813_818dup, results in the insertion of 2 amino acid(s) of the SURF1 protein (p.His271_Leu272dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs782488388, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215239). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824677	SCV002074342	uncertain significance	not specified	2022-01-19	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.813_818dupTCTGCA (p.His271_Leu272dup) results in an in-frame duplication that is predicted to duplicate 2 amino acids into the encoded protein. The variant allele was found at a frequency of 6.1e-05 in 245690 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SURF1 causing Leigh Syndrome (6.1e-05 vs 0.0018), allowing no conclusion about variant significance. c.813_818dupTCTGCA has been reported in the literature in heterozygous individuals undergoing preconception carrier screening (Capalbo_2019). This report does not provide any conclusions about association of the variant with Leigh Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.