Submissions for variant NM_025137.4(SPG11):c.808G>A (p.Val270Ile)

gnomAD frequency: 0.00845  dbSNP: rs80338868

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034267	SCV000290934	benign	Hereditary spastic paraplegia 11	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000584925	SCV000521191	benign	not provided	2019-08-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18079167, 25588603, 20301389)
CeGaT Center for Human Genetics Tuebingen	RCV000584925	SCV000692811	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SPG11: BP4, BS2
Eurofins Ntd Llc (ga)	RCV000439715	SCV000705273	likely benign	not specified	2017-01-25	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000034267	SCV000743951	benign	Hereditary spastic paraplegia 11	2014-10-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000034267	SCV001274095	likely benign	Hereditary spastic paraplegia 11	2017-06-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Athena Diagnostics Inc	RCV000439715	SCV001474778	benign	not specified	2019-10-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847640	SCV002105785	benign	Hereditary spastic paraplegia	2021-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439715	SCV002570953	benign	not specified	2022-07-01	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.808G>A (p.Val270Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0062 in 282816 control chromosomes (gnomAD), including 6 homozygotes. The variant occurs predominantly at a frequency of 0.009 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.808G>A has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia, however it was considered likely to be a polymorphism as it was found at a slightly higher frequency in healthy controls (Stevanin_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002415457	SCV002678510	likely benign	Inborn genetic diseases	2019-07-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV002467537	SCV002764209	likely benign	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467538	SCV002764210	likely benign	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000034267	SCV002764211	likely benign	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034267	SCV000733447	likely benign	Hereditary spastic paraplegia 11		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034267	SCV000745916	likely benign	Hereditary spastic paraplegia 11	2016-09-06	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000439715	SCV001808974	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000439715	SCV001924312	benign	not specified		no assertion criteria provided	clinical testing