NM_003119.4(SPG7):c.2271del (p.Met757fs) AND Hereditary spastic paraplegia 7

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000625997.10

Allele description [Variation Report for NM_003119.4(SPG7):c.2271del (p.Met757fs)]

NM_003119.4(SPG7):c.2271del (p.Met757fs)

Gene:

SPG7:SPG7 matrix AAA peptidase subunit, paraplegin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_003119.4(SPG7):c.2271del (p.Met757fs)

HGVS:

NC_000016.10:g.89556976del
NG_008082.1:g.53580del
NM_001363850.1:c.*49del
NM_003119.4:c.2271delMANE SELECT
NP_003110.1:p.Met757fs
NC_000016.9:g.89623384del
NM_003119.2:c.2271delG
NM_003119.3:c.2271del
p.M757fs

Protein change:

M757fs

Links:

dbSNP: rs1217391623

NCBI 1000 Genomes Browser:

rs1217391623

Molecular consequence:

NM_001363850.1:c.*49del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_003119.4:c.2271del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hereditary spastic paraplegia 7 (SPG7)
Synonyms:: Spastic paraplegia 7; Hereditary spastic paraplegia Paraplegin type; Autosomal recessive spastic paraplegia type 7
Identifiers:: MONDO: MONDO:0011803; MedGen: C1846564; Orphanet: 99013; OMIM: 607259

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000746603	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001216339	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27557734, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000746603

Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 8, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001216339

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 23, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
White	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

SPG7 and Impaired Emotional Communication.

Zhang L, McFarland KN, Subramony SH, Heilman KM, Ashizawa T.

Cerebellum. 2017 Apr;16(2):595-598. doi: 10.1007/s12311-016-0818-5. Erratum in: Cerebellum. 2017 Dec;16(5-6):991. doi: 10.1007/s12311-017-0901-6.

PubMed [citation]

PMID:: 27557734
PMCID:: PMC5325812

See all PubMed Citations (3)

Details of each submission

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746603.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

#	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	(GTR000553916.1)	1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001216339.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 522825). This frameshift has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 27557734; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the SPG7 gene (p.Met757Ilefs*66). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the SPG7 protein and extend the protein by 26 additional amino acid residues.

#	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

Last Updated: Sep 29, 2024

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