NM_001385875.1(ZFYVE27):c.572G>T (p.Gly191Val) AND Hereditary spastic paraplegia 33

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: May 28, 2019
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000001352.15

Allele description [Variation Report for NM_001385875.1(ZFYVE27):c.572G>T (p.Gly191Val)]

NM_001385875.1(ZFYVE27):c.572G>T (p.Gly191Val)

Gene:

ZFYVE27:zinc finger FYVE-type containing 27 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q24.2

Genomic location:

Preferred name:

NM_001385875.1(ZFYVE27):c.572G>T (p.Gly191Val)

HGVS:

NC_000010.11:g.97749494G>T
NG_017075.1:g.17374G>T
NM_001002261.4:c.572G>T
NM_001002262.4:c.572G>T
NM_001174119.2:c.476G>T
NM_001174120.2:c.314G>T
NM_001174121.2:c.278G>T
NM_001174122.2:c.218G>T
NM_001385871.1:c.572G>T
NM_001385875.1:c.572G>TMANE SELECT
NM_001385876.1:c.611G>T
NM_001385877.1:c.572G>T
NM_001385878.1:c.572G>T
NM_001385879.1:c.572G>T
NM_001385880.1:c.572G>T
NM_001385881.1:c.536G>T
NM_001385882.1:c.572G>T
NM_001385883.1:c.572G>T
NM_001385884.1:c.572G>T
NM_001385885.1:c.476G>T
NM_001385886.1:c.476G>T
NM_001385887.1:c.476G>T
NM_001385888.1:c.476G>T
NM_001385889.1:c.476G>T
NM_001385890.1:c.368G>T
NM_001385891.1:c.368G>T
NM_001385892.1:c.368G>T
NM_001385893.1:c.368G>T
NM_001385894.1:c.368G>T
NM_001385895.1:c.368G>T
NM_001385896.1:c.368G>T
NM_001385897.1:c.368G>T
NM_001385898.1:c.368G>T
NM_001385899.1:c.335G>T
NM_001385900.1:c.335G>T
NM_001385901.1:c.314G>T
NM_001385902.1:c.314G>T
NM_001385903.1:c.335G>T
NM_001385904.1:c.335G>T
NM_001385905.1:c.335G>T
NM_001385906.1:c.314G>T
NM_001385908.1:c.314G>T
NM_001385911.1:c.314G>T
NM_001385915.1:c.278G>T
NM_001385916.1:c.239G>T
NM_001385918.1:c.218G>T
NM_001385919.1:c.32-837G>T
NM_144588.7:c.572G>T
NP_001002261.1:p.Gly191Val
NP_001002261.1:p.Gly191Val
NP_001002262.1:p.Gly191Val
NP_001167590.1:p.Gly159Val
NP_001167591.1:p.Gly105Val
NP_001167592.1:p.Gly93Val
NP_001167593.1:p.Gly73Val
NP_001372800.1:p.Gly191Val
NP_001372804.1:p.Gly191Val
NP_001372805.1:p.Gly204Val
NP_001372806.1:p.Gly191Val
NP_001372807.1:p.Gly191Val
NP_001372808.1:p.Gly191Val
NP_001372809.1:p.Gly191Val
NP_001372810.1:p.Gly179Val
NP_001372811.1:p.Gly191Val
NP_001372812.1:p.Gly191Val
NP_001372813.1:p.Gly191Val
NP_001372814.1:p.Gly159Val
NP_001372815.1:p.Gly159Val
NP_001372816.1:p.Gly159Val
NP_001372817.1:p.Gly159Val
NP_001372818.1:p.Gly159Val
NP_001372819.1:p.Gly123Val
NP_001372820.1:p.Gly123Val
NP_001372821.1:p.Gly123Val
NP_001372822.1:p.Gly123Val
NP_001372823.1:p.Gly123Val
NP_001372824.1:p.Gly123Val
NP_001372825.1:p.Gly123Val
NP_001372826.1:p.Gly123Val
NP_001372827.1:p.Gly123Val
NP_001372828.1:p.Gly112Val
NP_001372829.1:p.Gly112Val
NP_001372830.1:p.Gly105Val
NP_001372831.1:p.Gly105Val
NP_001372832.1:p.Gly112Val
NP_001372833.1:p.Gly112Val
NP_001372834.1:p.Gly112Val
NP_001372835.1:p.Gly105Val
NP_001372837.1:p.Gly105Val
NP_001372840.1:p.Gly105Val
NP_001372844.1:p.Gly93Val
NP_001372845.1:p.Gly80Val
NP_001372847.1:p.Gly73Val
NP_653189.3:p.Gly191Val
NC_000010.10:g.99509251G>T
NM_001002261.3:c.572G>T
NR_169794.1:n.742G>T
NR_169795.1:n.700G>T
NR_169796.1:n.767G>T
NR_169798.1:n.731G>T
NR_169799.1:n.388G>T
NR_169801.1:n.767G>T
NR_169802.1:n.413G>T
NR_169803.1:n.742G>T
NR_169804.1:n.760G>T
NR_169805.1:n.771G>T
NR_169806.1:n.756G>T
NR_169808.1:n.799G>T
NR_169809.1:n.696G>T
NR_169810.1:n.767G>T
NR_169811.1:n.731G>T
Q5T4F4:p.Gly191Val

Protein change:

G105V; GLY191VAL

Links:

UniProtKB: Q5T4F4#VAR_027269; OMIM: 610243.0001; dbSNP: rs35077384

NCBI 1000 Genomes Browser:

rs35077384

Molecular consequence:

NM_001385919.1:c.32-837G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001002261.4:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002262.4:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174119.2:c.476G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174120.2:c.314G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174121.2:c.278G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174122.2:c.218G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385871.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385875.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385876.1:c.611G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385877.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385878.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385879.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385880.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385881.1:c.536G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385882.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385883.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385884.1:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385885.1:c.476G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385886.1:c.476G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385887.1:c.476G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385888.1:c.476G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385889.1:c.476G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385890.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385891.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385892.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385893.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385894.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385895.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385896.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385897.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385898.1:c.368G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385899.1:c.335G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385900.1:c.335G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385901.1:c.314G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385902.1:c.314G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385903.1:c.335G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385904.1:c.335G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385905.1:c.335G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385906.1:c.314G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385908.1:c.314G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385911.1:c.314G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385915.1:c.278G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385916.1:c.239G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385918.1:c.218G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_144588.7:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_169794.1:n.742G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169795.1:n.700G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169796.1:n.767G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169798.1:n.731G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169799.1:n.388G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169801.1:n.767G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169802.1:n.413G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169803.1:n.742G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169804.1:n.760G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169805.1:n.771G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169806.1:n.756G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169808.1:n.799G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169809.1:n.696G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169810.1:n.767G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_169811.1:n.731G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary spastic paraplegia 33
Synonyms:: SPASTIC PARAPLEGIA 33, AUTOSOMAL DOMINANT
Identifiers:: MONDO: MONDO:0012448; MedGen: C1853251; OMIM: 610244

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021502	OMIM	no assertion criteria provided	Pathogenic (May 9, 2014)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 16826525, 18606302, 24668814 Mannan, A. U. Response to Martignoni et al. (Letter) Am. J. Hum. Genet. 83: 128-130, 2008.,
SCV000366369	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Apr 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24668814, 16826525, 18606302 Citation Link,
SCV001138156	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001369545	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Protrudin regulates endoplasmic reticulum morphology and function associated with the pathogenesis of hereditary spastic paraplegia.

Hashimoto Y, Shirane M, Matsuzaki F, Saita S, Ohnishi T, Nakayama KI.

J Biol Chem. 2014 May 9;289(19):12946-61. doi: 10.1074/jbc.M113.528687. Epub 2014 Mar 25.

PubMed [citation]

PMID:: 24668814
PMCID:: PMC4036311

ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia.

Mannan AU, Krawen P, Sauter SM, Boehm J, Chronowska A, Paulus W, Neesen J, Engel W.

Am J Hum Genet. 2006 Aug;79(2):351-7. Epub 2006 Jun 1.

PubMed [citation]

PMID:: 16826525
PMCID:: PMC1559503

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000021502.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In affected members of a 5-generation German family with hereditary spastic paraplegia (SPG33; 610244), Mannan et al. (2006) found a G-to-T transversion at position 572 in exon 6 of the ZFYVE27 cDNA. The mutation produced a gly191-to-val (G191V) substitution. The G191V mutation (G105V in isoform c of the protein) is located near the third transmembrane motif and shifts the transmembrane motif forward by 3 amino acids. Mannan et al. (2006) observed that expression of the mutated protein showed an aberrant intracellular pattern in tubular structures and that its interaction with spastin was severely affected.

Martignoni et al. (2008) commented that they found no difference in the ability of wildtype or G191V-mutant protrudin to extend neurites in cellular functional expression studies. The G191V-mutant protein was also found to interact with Rab11-GDP (605570) and spastin (604277), indicating that the mutation did not lead to loss of function. Martignoni et al. (2008) stated that G191V (rs35077384) had been identified as a SNP in several populations, with an allele frequency ranging from 0.008 to 0.067, thus casting doubt on the pathogenicity of this mutation. Mannan (2008) replied that their studies showed a decreased interaction between G191V-mutant protrudin and spastin and explained that discrepancies could be due to the different assays used or the variable effect of G191V-mutant protrudin in different ethnic populations.

Hashimoto et al. (2014) found that expression of G191V-mutant human protrudin mildly enhanced the sensitivity of mouse Neuro2a neuroblasts to several cell stressors. G191V-mutant protrudin had a markedly longer half-life and was detected in larger protein complexes than wildtype protrudin.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000366369.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001138156.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001369545.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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