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NM_003060.4(SLC22A5):c.1463G>A (p.Arg488His) AND not specified

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Mar 16, 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:
RCV000826038.16

Allele description [Variation Report for NM_003060.4(SLC22A5):c.1463G>A (p.Arg488His)]

NM_003060.4(SLC22A5):c.1463G>A (p.Arg488His)

Gene:
SLC22A5:solute carrier family 22 member 5 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q31.1
Genomic location:
Preferred name:
NM_003060.4(SLC22A5):c.1463G>A (p.Arg488His)
HGVS:
  • NC_000005.10:g.132393688G>A
  • NG_008982.2:g.28985G>A
  • NM_001308122.2:c.1535G>A
  • NM_003060.4:c.1463G>AMANE SELECT
  • NP_001295051.1:p.Arg512His
  • NP_001295051.1:p.Arg512His
  • NP_003051.1:p.Arg488His
  • NP_003051.1:p.Arg488His
  • NC_000005.9:g.131729380G>A
  • NM_001308122.1:c.1535G>A
  • NM_003060.3:c.1463G>A
  • O76082:p.Arg488His
Protein change:
R488H
Links:
UniProtKB: O76082#VAR_066846; dbSNP: rs28383481
NCBI 1000 Genomes Browser:
rs28383481
Molecular consequence:
  • NM_001308122.2:c.1535G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003060.4:c.1463G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000967529Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Uncertain significance
(Sep 17, 2018)
germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV001983565Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely benign
(Mar 16, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided21not providednot providednot providedclinical testing

Citations

PubMed

Pharmacological rescue of carnitine transport in primary carnitine deficiency.

Amat di San Filippo C, Pasquali M, Longo N.

Hum Mutat. 2006 Jun;27(6):513-23.

PubMed [citation]
PMID:
16652335

Cardiomyopathy and carnitine deficiency.

Amat di San Filippo C, Taylor MR, Mestroni L, Botto LD, Longo N.

Mol Genet Metab. 2008 Jun;94(2):162-6. doi: 10.1016/j.ymgme.2008.02.002. Epub 2008 Mar 11.

PubMed [citation]
PMID:
18337137
PMCID:
PMC2430214
See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967529.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (15)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Arg488His var iant in SLC22A5 has been reported in the compound heterozgous state in at least 5 individuals with primary carnitine deficiency (di San Filippo 2006, Mazzini 20 11, Rose 2012, Frigeni 2017, Thompson 2018); however in all of these individuals a second variant (p.Ala142Ser) was identified on the same copy of the SLC22A5 g ene (in cis). Functional studies indicate that p.Arg488His does not significantl y impact carnitine transport alone, and must occur in cis with p.Ala142Ser to im pact protein function (di San Filippo 2006). However, these types of assays may not accurately represent biological function. The p.Arg488His variant has been i dentified in 0.47% (598/126640) of European chromosomes and 0.32% (884/277154) o f total chromosomes by the Genome Aggregation Database, including 6 homozygotes (gnomAD, http://gnomad.broadinstitute.org). It is also present in ClinVar with c onfliciting interpretations of pathogenicity (Variation ID# 38794). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact the protein. Finally, another variant at the same position ( p.Arg488Cys) has been identified in the homozygous state in one individual with primary carnitine deficiency (Schimmenti 2007). In summary, while the clinical s ignificance of this variant is uncertain, these data suggest that, in the absenc e of p.Ala142Ser, the p.Arg488His variant is unlikely to be disease causing. AMC G/AMP criteria applied: PS4_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983565.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: SLC22A5 c.1463G>A (p.Arg488His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251442 control chromosomes, predominantly at a frequency of 0.0048 within the Latino subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1463G>A has been reported to be in cis with c.424G>T (pathogenic) in the literature in at least one individual affected with Systemic Primary Carnitine Deficiency (e.g. Amat di San Filippo_2006). The variant has been reported in at least one patient with Hypoketotic hypoglycemia and Abnormality of carnitine metabolism, in trans with a VUS (Barbosa-Gouveia_2021). In addition, c.1463G>A in isolation has been reported in general population and is not in linkage disequilibrium with c.424G>T (gnomAD database, Toh_2010). Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of wild type Carnitine transport activity (Amat di San Filippo_2006, Frigeni_2017). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=3, VUS n=9, benign/likely benign n=3). Based on the evidence outlined above, the variant in isolation was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024