NM_033409.4(SLC52A3):c.211G>A (p.Glu71Lys) AND Brown-Vialetto-van Laere syndrome 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 8, 2023
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:: RCV000191960.4

Allele description [Variation Report for NM_033409.4(SLC52A3):c.211G>A (p.Glu71Lys)]

NM_033409.4(SLC52A3):c.211G>A (p.Glu71Lys)

Gene:

SLC52A3:solute carrier family 52 member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20p13

Genomic location:

Preferred name:

NM_033409.4(SLC52A3):c.211G>A (p.Glu71Lys)

HGVS:

NC_000020.11:g.765564C>T
NG_027687.2:g.15422G>A
NM_001370085.1:c.211G>A
NM_001370086.1:c.211G>A
NM_033409.4:c.211G>AMANE SELECT
NP_001357014.1:p.Glu71Lys
NP_001357015.1:p.Glu71Lys
NP_212134.3:p.Glu71Lys
LRG_1394t1:c.211G>A
LRG_1394:g.15422G>A
LRG_1394p1:p.Glu71Lys
NC_000020.10:g.746208C>T
NG_027687.1:g.8021G>A
NM_033409.3:c.211G>A
Q9NQ40:p.Glu71Lys

Protein change:

E71K; Glu71Lys

Links:

UniProtKB: Q9NQ40#VAR_077426; dbSNP: rs267606683

NCBI 1000 Genomes Browser:

rs267606683

Molecular consequence:

NM_001370085.1:c.211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370086.1:c.211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033409.4:c.211G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Brown-Vialetto-van Laere syndrome 1
Synonyms:: BULBAR PALSY, PROGRESSIVE, WITH SENSORINEURAL DEAFNESS; PONTOBULBAR PALSY WITH DEAFNESS; Pontobulbar palsy and neurosensory deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0024537; MedGen: C0796274; Orphanet: 97229; OMIM: 211530

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000246212	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003924334	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 8, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004298452	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22273710, 20920669, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000246212

GeneReviews

no classification provided

not provided

germline

literature only

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

SCV003924334

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 8, 2023)

germline

research

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

SCV004298452

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 14, 2023)

germline

clinical testing

PubMed (3)
[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	literature only, research
not provided	germline	unknown	not provided	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

Effect of clinical mutations on functionality of the human riboflavin transporter-2 (hRFT-2).

Nabokina SM, Subramanian VS, Said HM.

Mol Genet Metab. 2012 Apr;105(4):652-7. doi: 10.1016/j.ymgme.2011.12.021. Epub 2012 Jan 5.

PubMed [citation]

PMID:: 22273710
PMCID:: PMC3309148

See all PubMed Citations (4)

Details of each submission

From GeneReviews, SCV000246212.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV003924334.1

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

#	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 Invitae, SCV004298452.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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. Experimental studies have shown that this missense change affects SLC52A3 function (PMID: 22273710). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC52A3 protein function. ClinVar contains an entry for this variant (Variation ID: 210015). This missense change has been observed in individual(s) with Brown-Vialetto-Van Laere syndrome (PMID: 20920669). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs267606683, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 71 of the SLC52A3 protein (p.Glu71Lys).

#	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: Feb 20, 2024

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