NM_181507.2(HPS5):c.1940T>C (p.Leu647Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 18, 2022
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:: RCV002044983.4

Allele description [Variation Report for NM_181507.2(HPS5):c.1940T>C (p.Leu647Ser)]

NM_181507.2(HPS5):c.1940T>C (p.Leu647Ser)

Gene:

HPS5:HPS5 biogenesis of lysosomal organelles complex 2 subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.1

Genomic location:

Preferred name:

NM_181507.2(HPS5):c.1940T>C (p.Leu647Ser)

HGVS:

NC_000011.10:g.18291942A>G
NG_008877.1:g.35233T>C
NM_007216.4:c.1598T>C
NM_181507.2:c.1940T>CMANE SELECT
NM_181508.1:c.1598T>C
NP_009147.3:p.Leu533Ser
NP_852608.1:p.Leu647Ser
NP_852609.1:p.Leu533Ser
LRG_586t1:c.1940T>C
LRG_586:g.35233T>C
NC_000011.9:g.18313489A>G
NM_181507.1:c.1940T>C
NM_181507.2:c.1940T>C

Protein change:

L533S

Links:

dbSNP: rs781166596

NCBI 1000 Genomes Browser:

rs781166596

Molecular consequence:

NM_007216.4:c.1598T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181507.2:c.1940T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181508.1:c.1598T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002112765	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002757653	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 26, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002112765

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 18, 2022)

germline

clinical testing

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

SCV002757653

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 26, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002112765.2

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 647 of the HPS5 protein (p.Leu647Ser). This variant is present in population databases (rs781166596, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HPS5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1351770). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

#	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 GeneDx, SCV002757653.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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

Last Updated: Sep 29, 2024

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