NM_183050.4(BCKDHB):c.1022T>A (p.Ile341Asn) AND Maple syrup urine disease

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 8, 2023
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:: RCV000209023.6

Allele description [Variation Report for NM_183050.4(BCKDHB):c.1022T>A (p.Ile341Asn)]

NM_183050.4(BCKDHB):c.1022T>A (p.Ile341Asn)

Gene:

BCKDHB:branched chain keto acid dehydrogenase E1 subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q14.1

Genomic location:

Preferred name:

NM_183050.4(BCKDHB):c.1022T>A (p.Ile341Asn)

Other names:

p.I341N:ATC>AAC

HGVS:

NC_000006.12:g.80273205T>A
NG_009775.2:g.171579T>A
NM_000056.5:c.1022T>A
NM_001318975.1:c.812T>A
NM_183050.4:c.1022T>AMANE SELECT
NP_000047.1:p.Ile341Asn
NP_001305904.1:p.Ile271Asn
NP_898871.1:p.Ile341Asn
NC_000006.11:g.80982922T>A
NM_000056.3:c.1022T>A
NM_183050.2:c.1022T>A
NR_134945.2:n.1139T>A

Protein change:

I271N

Links:

dbSNP: rs796051939

NCBI 1000 Genomes Browser:

rs796051939

Molecular consequence:

NM_000056.5:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318975.1:c.812T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_183050.4:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134945.2:n.1139T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Maple syrup urine disease (MSUD)
Identifiers:: MONDO: MONDO:0009563; MeSH: D008375; MedGen: C0024776; Orphanet: 511; OMIM: PS248600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000240036	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (Submitter's publication)	Pathogenic (Jan 1, 2012)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002033166	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004294638	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26257134, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000240036

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

criteria provided, single submitter

(Submitter's publication)

Pathogenic
(Jan 1, 2012)

germline

research

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

SCV002033166

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 7, 2021)

germline

clinical testing

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

SCV004294638

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (2)
[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	1	not provided	not provided	not provided	not provided	research
not provided	germline	no	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

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

Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients.

Gupta D, Bijarnia-Mahay S, Saxena R, Kohli S, Dua-Puri R, Verma J, Thomas E, Shigematsu Y, Yamaguchi S, Deb R, Verma IC.

Eur J Med Genet. 2015 Sep;58(9):471-8. doi: 10.1016/j.ejmg.2015.08.002. Epub 2015 Aug 7.

PubMed [citation]

PMID:: 26257134

See all PubMed Citations (3)

Details of each submission

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV000240036.1

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

From Genome-Nilou Lab, SCV002033166.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294638.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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. 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 BCKDHB protein function. ClinVar contains an entry for this variant (Variation ID: 203639). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 26257134). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 341 of the BCKDHB protein (p.Ile341Asn).

#	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: Sep 29, 2024

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