VCV001341352.28 - ClinVar

NM_021095.4(SLC5A6):c.1285A>G (p.Ser429Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021095.4(SLC5A6):c.1285A>G (p.Ser429Gly)

Variation ID: 1341352 Accession: VCV001341352.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 27202065 (GRCh38) [ NCBI UCSC ] 2: 27424933 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 13, 2022	Nov 17, 2024	Sep 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_021095.4:c.1285A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066918.2:p.Ser429Gly	missense
NM_021095.4:c.1285A>Gtransition MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		missense
NM_021095.2:c.1285A>G
NR_028323.2:n.2093A>G		non-coding transcript variant
NC_000002.12:g.27202065T>C
NC_000002.11:g.27424933T>C

... more HGVS ... less HGVS

Protein change

S429G

Other names

Canonical SPDI

NC_000002.12:27202064:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 604024.0007 dbSNP: rs2147992303 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC5A6		-	-	GRCh38 GRCh37	82	112

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neurodegeneration, infantile-onset, biotin-responsive	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 27, 2024	RCV001834557.6
Peripheral motor neuropathy, childhood-onset, biotin-responsive	Likely pathogenic (2)	criteria provided, single submitter	-	RCV002259403.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodegeneration, infantile-onset, biotin-responsive (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Suma Genomics Accession: SCV002097017.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Likely pathogenic (Dec 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Neurodegeneration, infantile-onset, biotin-responsive Affected status: yes Allele origin: maternal	Kids Research, The Children's Hospital at Westmead Accession: SCV002759307.1 First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023
Likely pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodegeneration, infantile-onset, biotin-responsive (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768890.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration, infantile-onset, biotin-responsive (MIM#618973). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SSF domain (DECIPHER, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0903 - This variant has limited evidence for segregation with disease. It was reported in a similarly affected paternal uncle. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using this individual's fibroblasts (compound heterozygous with c.393+2T>C) demonstrated both markedly reduced mRNA expression and biotin uptake (personal communication). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_021095.2:c.393+2T>C; p.(Val5_Glu131del) or p.(Glu131_Tyr132ins22*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peripheral motor neuropathy, childhood-onset, biotin-responsive (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Suma Genomics Accession: SCV003852619.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Sep 27, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Neurodegeneration, infantile-onset, biotin-responsive Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005394120.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (1) PubMed: 35013551 Comment: Variant summary: SLC5A6 c.1285A>G (p.Ser429Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: SLC5A6 c.1285A>G (p.Ser429Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251426 control chromosomes. c.1285A>G has been reported in the literature in three homozygous siblings and a fourth unrelated homozygous individual affected with biotin-responsive motor neuropathy (e.g. Holling_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 35013551). ClinVar contains an entry for this variant (Variation ID: 1341352). . Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 02, 2022)	no assertion criteria provided Method: literature only	PERIPHERAL MOTOR NEUROPATHY, CHILDHOOD-ONSET, BIOTIN-RESPONSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV002524117.1 First in ClinVar: Jun 10, 2022 Last updated: Jun 10, 2022	Publications: PubMed (1) PubMed: 35013551 Comment on evidence: In 3 sibs (family 1) and an unrelated patient (family 3) with childhood-onset biotin-responsive peripheral motor neuropathy (COMNB; 619903), Holling et al. (2022) identified a … (more) In 3 sibs (family 1) and an unrelated patient (family 3) with childhood-onset biotin-responsive peripheral motor neuropathy (COMNB; 619903), Holling et al. (2022) identified a homozygous c.1285A-G transition (c.1285A-G transition, NM_021095.4) in the SLC5A6 gene, resulting in a ser429-to-gly (S429G) substitution in transmembrane domain 11. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Haplotype analysis suggested parental consanguinity in both families, as well as remote relatedness between the 2 families. Transfection of the S429G mutation into HeLa cells showed that the mutant protein localized normally to the plasma membrane, leading the authors to suggest that the variant may impair transporter function. In addition to distal upper limb muscle weakness due to peripheral motor neuropathy, the patient from family 3 also had mild cerebellar signs, proximal muscle weakness, and a spastic-ataxic gait. (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration, infantile-onset, biotin-responsive (MIM#618973). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SSF domain (DECIPHER, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0903 - This variant has limited evidence for segregation with disease. It was reported in a similarly affected paternal uncle. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using this individual's fibroblasts (compound heterozygous with c.393+2T>C) demonstrated both markedly reduced mRNA expression and biotin uptake (personal communication). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_021095.2:c.393+2T>C; p.(Val5_Glu131del) or p.(Glu131_Tyr132ins22*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Variant summary: SLC5A6 c.1285A>G (p.Ser429Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251426 control chromosomes. c.1285A>G has been reported in the literature in three homozygous siblings and a fourth unrelated homozygous individual affected with biotin-responsive motor neuropathy (e.g. Holling_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 35013551). ClinVar contains an entry for this variant (Variation ID: 1341352). . Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)	Method not provided	Result not provided	Kids Research, The Children's Hospital at Westmead Accession: SCV002759307.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel biallelic variants expand the SLC5A6-related phenotypic spectrum.	Holling T	European journal of human genetics : EJHG	2022	PMID: 35013551

Text-mined citations for rs2147992303 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_021095.4(SLC5A6):c.1285A>G (p.Ser429Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2147992303 ...