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NM_015915.5(ATL1):c.740A>G (p.His247Arg) AND Hereditary spastic paraplegia 3A

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Sep 17, 2022
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:
RCV001376177.5

Allele description [Variation Report for NM_015915.5(ATL1):c.740A>G (p.His247Arg)]

NM_015915.5(ATL1):c.740A>G (p.His247Arg)

Gene:
ATL1:atlastin GTPase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q22.1
Genomic location:
Preferred name:
NM_015915.5(ATL1):c.740A>G (p.His247Arg)
HGVS:
  • NC_000014.9:g.50614389A>G
  • NG_009028.1:g.86308A>G
  • NM_001127713.1:c.740A>G
  • NM_015915.5:c.740A>GMANE SELECT
  • NM_181598.4:c.740A>G
  • NP_001121185.1:p.His247Arg
  • NP_056999.2:p.His247Arg
  • NP_853629.2:p.His247Arg
  • LRG_360t1:c.740A>G
  • LRG_360t2:c.740A>G
  • LRG_360:g.86308A>G
  • LRG_360p2:p.His247Arg
  • NC_000014.8:g.51081107A>G
  • NM_015915.4:c.740A>G
Protein change:
H247R
Links:
dbSNP: rs2140226883
NCBI 1000 Genomes Browser:
rs2140226883
Molecular consequence:
  • NM_001127713.1:c.740A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015915.5:c.740A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181598.4:c.740A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary spastic paraplegia 3A (SPG3A)
Synonyms:
SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; FAMILIAL SPASTIC PARAPLEGIA, AUTOSOMAL DOMINANT, 1; SPG3; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008437; MedGen: C2931355; Orphanet: 100984; OMIM: 182600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001573127Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(May 5, 2021)
germlineclinical testing

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

SCV003442284Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Sep 17, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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
See all PubMed Citations (5)

Details of each submission

From Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, SCV001573127.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providedclinical testing PubMed (1)

Description

To our knowledge, this sequence variant has not been reported in the literature or in control databases. However, a sequence variant affecting the same nuceotide, c.740A>C, p.(His247Pro), has previously been reported as causing SPG3 (Nameka 2006, Abel, 2004). The detected variant segregates with the disease in the family. We therefore classify it as being likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV003442284.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.His247 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been observed in individuals with ATL1-related conditions (PMID: 14695538), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1065628). This missense change has been observed in individual(s) with ATL1-related conditions (PMID: 19459885, 26671083). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 247 of the ATL1 protein (p.His247Arg).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 14, 2024