NM_000520.6(HEXA):c.1264C>G (p.Leu422Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 12, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001356326.14

Allele description [Variation Report for NM_000520.6(HEXA):c.1264C>G (p.Leu422Val)]

NM_000520.6(HEXA):c.1264C>G (p.Leu422Val)

Gene:

HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q23

Genomic location:

Preferred name:

NM_000520.6(HEXA):c.1264C>G (p.Leu422Val)

HGVS:

NC_000015.10:g.72346593G>C
NG_009017.2:g.34587C>G
NM_000520.6:c.1264C>GMANE SELECT
NM_000520.6:c.1264C>G
NM_001318825.2:c.1297C>G
NP_000511.2:p.Leu422Val
NP_001305754.1:p.Leu433Val
NC_000015.9:g.72638934G>C
NG_009017.1:g.34587C>G
NM_000520.4:c.1264C>G

Protein change:

L422V

Links:

dbSNP: rs774562271

NCBI 1000 Genomes Browser:

rs774562271

Molecular consequence:

NM_000520.6:c.1264C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1297C>G - 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
SCV001551461	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV002050255	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Oct 12, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001551461

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV002050255

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Oct 12, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551461.1

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

Description

The HEXA p.Leu422Val variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs774562271) and in control databases in 4 of 251460 chromosomes at a frequency of 0.00001591 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the Latino population in 4 of 34592 chromosomes (freq: 0.000116), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Leu422 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of 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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002050255.1

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

Description

The HEXA c.1264C>G; p.Leu422Val variant (rs774562271), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 841751). This variant is found in the Latino population with an overall allele frequency of 0.01% (4/34592 alleles) in the Genome Aggregation Database. The leucine at codon 422 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.845). Additionally, computational analyses of splicing (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site, although RNA studies would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Leu422Val variant is uncertain at this time.

#	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: Oct 26, 2024

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