NM_002340.6(LSS):c.1194+5G>A AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 12, 2024
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:: RCV001784569.10

Allele description [Variation Report for NM_002340.6(LSS):c.1194+5G>A]

NM_002340.6(LSS):c.1194+5G>A

Gene:

LSS:lanosterol synthase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_002340.6(LSS):c.1194+5G>A

HGVS:

NC_000021.9:g.46210683C>T
NG_011510.1:g.23142G>A
NM_001001438.2:c.1194+5G>A
NM_001001438.3:c.1194+5G>A
NM_001145436.2:c.1161+5G>A
NM_001145437.2:c.954+5G>A
NM_002340.6:c.1194+5G>AMANE SELECT
NC_000021.8:g.47630597C>T
NM_002340.5:c.1194+5G>A

Nucleotide change:

IVS12, G-A, +5

Links:

OMIM: 600909.0013; dbSNP: rs748758448

NCBI 1000 Genomes Browser:

rs748758448

Molecular consequence:

NM_001001438.3:c.1194+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001145436.2:c.1161+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001145437.2:c.954+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_002340.6:c.1194+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002586856	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 12, 2024)	germline	clinical testing	Citation Link,
SCV003787184	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17576681, 9536098, 30723320, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002586856

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Dec 12, 2024)

germline

clinical testing

Citation Link,

SCV003787184

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 12, 2023)

germline

clinical testing

PubMed (4)
[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	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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV002586856.3

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

Description

Observed with a second LSS variant on the opposite allele (in trans) in two siblings with LSS-related clinical features in published literature (PMID: 30723320); Published functional studies suggest a damaging effect with complete in-frame skipping of exon 12 (PMID: 30723320); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 34426522, 30723320)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003787184.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant has been observed in individual(s) with LSS-related conditions (PMID: 30723320). It has also been observed to segregate with disease in related individuals. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 30723320). ClinVar contains an entry for this variant (Variation ID: 834067). This variant is present in population databases (rs748758448, gnomAD 0.01%). This sequence change falls in intron 12 of the LSS gene. It does not directly change the encoded amino acid sequence of the LSS protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.

#	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: Jan 13, 2025

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