Submissions for variant NM_003119.4(SPG7):c.679C>T (p.Arg227Ter)

gnomAD frequency: 0.00001  dbSNP: rs764791523

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000276524	SCV000330502	pathogenic	not provided	2016-05-06	criteria provided, single submitter	clinical testing	The R227X pathogenic variant in the SPG7 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R227X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R227X as a pathogenic variant.
Paris Brain Institute, Inserm - ICM	RCV001391423	SCV001451032	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001391423	SCV001519204	pathogenic	Hereditary spastic paraplegia 7	2021-01-04	criteria provided, single submitter	research
Ambry Genetics	RCV002519056	SCV003560059	pathogenic	Inborn genetic diseases	2022-11-02	criteria provided, single submitter	clinical testing	The c.679C>T (p.R227*) alteration, located in exon 5 (coding exon 5) of the SPG7 gene, consists of a C to T substitution at nucleotide position 679. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 227. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (4/251496) total alleles studied. The highest observed frequency was 0.007% (2/30616) of South Asian alleles. This variant has been reported in conjunction with a second SPG7 variant in an individual with spastic paraplegia; however, the phase of the two variants was not specified (Martinuzzi, 2016; Galatolo, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001391423	SCV004296433	pathogenic	Hereditary spastic paraplegia 7	2023-02-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg227*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). This variant is present in population databases (rs764791523, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27077743). ClinVar contains an entry for this variant (Variation ID: 280575). For these reasons, this variant has been classified as Pathogenic.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV001391423	SCV005044515	pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786648	SCV005399539	pathogenic	Optic atrophy	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spastic paraplegia 7 (MIM#607259) and autosomal dominant optical atrophy (MONDO#0003608). There is currently no genotype-phenotype correlation in terms of variant types or location. While missense variants are mostly associated with autosomal dominant optical atrophy, two NMD-predicted variants have also been reported (PMID: 32548275). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 4 heterozygotes, 0 homozygotes.) (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It was one of two heterozygous variants identified in an individual with late onset autosomal recessive spastic paraplegia 7 (MIM#607259; PMID: 34445196) and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign