NM_000344.4(SMN1):c.785G>T (p.Ser262Ile) AND Kugelberg-Welander disease

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 19, 2020
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:: RCV000009736.7

Allele description [Variation Report for NM_000344.4(SMN1):c.785G>T (p.Ser262Ile)]

NM_000344.4(SMN1):c.785G>T (p.Ser262Ile)

Gene:

SMN1:survival of motor neuron 1, telomeric [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q13.2

Genomic location:

Preferred name:

NM_000344.4(SMN1):c.785G>T (p.Ser262Ile)

HGVS:

NC_000005.10:g.70946127G>T
NG_008691.1:g.26187G>T
NM_000344.4:c.785G>TMANE SELECT
NM_001297715.1:c.785G>T
NM_022874.2:c.689G>T
NP_000335.1:p.Ser262Ile
NP_000335.1:p.Ser262Ile
NP_001284644.1:p.Ser262Ile
NP_075012.1:p.Ser230Ile
LRG_676t1:c.785G>T
LRG_676:g.26187G>T
LRG_676p1:p.Ser262Ile
NC_000005.9:g.70241954G>T
NM_000344.3:c.785G>T
Q16637:p.Ser262Ile

Protein change:

S230I; SER262ILE

Links:

UniProtKB: Q16637#VAR_005616; OMIM: 600354.0003; dbSNP: rs1554066659

NCBI 1000 Genomes Browser:

rs1554066659

Molecular consequence:

NM_000344.4:c.785G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001297715.1:c.785G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022874.2:c.689G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Kugelberg-Welander disease (SMA3)
Synonyms:: SPINAL MUSCULAR ATROPHY, TYPE III; SMA III; Muscular atrophy, juvenile; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009672; MedGen: C0152109; Orphanet: 70; Orphanet: 83419; OMIM: 253400

Recent activity

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congested-like trachea protein [Adelges cooleyi]
congested-like trachea protein [Adelges cooleyi]
gi|2296681098|ref|XP_050426119.1|

Protein
MME1 [Drosophila erecta]
MME1 [Drosophila erecta]
Gene ID:6541616

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029957	OMIM	no assertion criteria provided	Pathogenic (May 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000924377	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 3, 2016)	maternal, unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9158159, 25741868
SCV002769536	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9158159, 9199562, 9668169, 10205265, 20301526, 23022347, 23073312, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000029957

OMIM

no assertion criteria provided

Pathogenic
(May 1, 1997)

germline

literature only

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

SCV000924377

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 3, 2016)

maternal, unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002769536

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 19, 2020)

germline

clinical testing

PubMed (8)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	no	1	not provided	not provided	1	not provided	clinical testing
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA).

Hahnen E, Schönling J, Rudnik-Schöneborn S, Raschke H, Zerres K, Wirth B.

Hum Mol Genet. 1997 May;6(5):821-5.

PubMed [citation]

PMID:: 9158159

Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number.

McAndrew PE, Parsons DW, Simard LR, Rochette C, Ray PN, Mendell JR, Prior TW, Burghes AH.

Am J Hum Genet. 1997 Jun;60(6):1411-22.

PubMed [citation]

PMID:: 9199562
PMCID:: PMC1716150

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000029957.2

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

Description

In a patient of Australian origin with SMA type III (253400), Hahnen et al. (1997) identified an AGT-to-ATT transversion in codon 262 of the SMN1 gene,resulting in a ser262-to-ile (S262I) amino acid substitution. The nonsense mutation was inherited from the father. The other allele was apparently the deleted SMN.

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

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000924377.1

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

Description

intermittent falls as a child, pain in legs upon climbing stairs, required use of upper extremities to stand from seated poistion, wheelchair dependent by 17 years old, upper and lower extremity weakness

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769536.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0106 - Variant is heterozygous. (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 – Population information is not available for this region in gnomAD. (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (SMN domain; NCBI, Decipher, PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. At least one alternative change in the same residue resulting in a glycine has been reported in a patient with type III spinal muscular atrophy (ClinVar; PMID: 23022347). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in patients with type III spinal muscular atrophy (ClinVar; PMID: 9158159; PMID: 23073312; PMID: 9199562). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant reduces RNA binding efficiency and impacts self-oligomerisation (PMID: 9668169; PMID: 23022347). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	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: Jun 23, 2024

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