Submissions for variant NM_003119.4(SPG7):c.1715C>T (p.Ala572Val)

gnomAD frequency: 0.00015  dbSNP: rs72547551

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neurogenetics of motion laboratory, Montreal Neurological Institute	RCV000235251	SCV000245721	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	case-control
GeneDx	RCV000413737	SCV000491195	pathogenic	not provided	2024-08-09	criteria provided, single submitter	clinical testing	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: 14985266, 23065789, 25681447, 26626314, 22571692, 25497598, Campins-Romeu2021[Case Report], 29246610, Haj Saleem2021[Case report], 29482223, 30533525, 32816195, 33059505, 34405107, 33624863, 37090936)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000235251	SCV000640072	pathogenic	Hereditary spastic paraplegia 7	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 572 of the SPG7 protein (p.Ala572Val). This variant is present in population databases (rs72547551, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 14985266, 23065789, 25681447, 26626314). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217269). 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 not expected to disrupt SPG7 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000413737	SCV001246899	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000413737	SCV001476955	pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
Genetic Services Laboratory, University of Chicago	RCV000413737	SCV002064529	pathogenic	not provided	2021-04-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1715C>T variant in exon 13 that results in an amino acid change, p.Ala572Val. This sequence change has been described in the gnomAD database with a low population frequency of 0.0036% (dbSNP rs72547551). This pathogenic sequence change has previously been described in several patients with SPG7-related spastic paraplegia and ataxia (Wilkinson et al., 2004; Klebe et al., 2012; Pfeffer et al., 2015; Choquet et al., 2015). The p.Ala572Val change affects a highly conserved amino acid residue located in a domain of the SPG7 protein that is known to be functional. The p.Ala572Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847906	SCV002105853	pathogenic	Hereditary spastic paraplegia	2021-11-16	criteria provided, single submitter	clinical testing
3billion	RCV000235251	SCV002573052	pathogenic	Hereditary spastic paraplegia 7	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217269). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14985266 , 23065789 , 25681447 , 26626314). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000235251	SCV002803485	pathogenic	Hereditary spastic paraplegia 7	2021-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235251	SCV004122197	pathogenic	Hereditary spastic paraplegia 7	2023-10-26	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1715C>T (p.Ala572Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251306 control chromosomes. c.1715C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Vural_2021, Burguez_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000235251	SCV005044580	pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000235251	SCV005399556	pathogenic	Hereditary spastic paraplegia 7	2023-07-16	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 spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO#0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 21 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Peptidase family M41 domain (DICPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic by clinical diagnostic laboratories and has also been identified as compound heterozygous in individuals with ataxia, cerebellar ataxia or hereditary spastic paraplegia (ClinVar, PMIDs: 26626314, 25681447, 29246610). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign