Submissions for variant NM_003060.4(SLC22A5):c.1412G>A (p.Arg471His)

dbSNP: rs386134223

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022382	SCV000632530	pathogenic	Renal carnitine transport defect	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 471 of the SLC22A5 protein (p.Arg471His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 14605509, 25132046). 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. ClinVar contains an entry for this variant (Variation ID: 25426). 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 SLC22A5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 16652335). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000022382	SCV001451664	likely pathogenic	Renal carnitine transport defect	2020-07-10	criteria provided, single submitter	clinical testing	The SLC22A5 c.1412G>A (p.Arg471His) variant, alternately known as c.1484G>A (p.Arg495His) when annotated on the NM_001308122.1 transcript, is a missense variant that has been reported in at least four individuals from two unrelated families with systemic primary carnitine deficiency (SPCD). Spiekerkoetter et al. (2003) describe a consanguineous Turkish family in which a father and two sons are homozygous for the p.Arg471His variant. All individuals displayed low serum carnitine and deficient carnitine uptake in fibroblasts, however only one son was symptomatic. Han et al. (2014) report a Chinese child with vomiting, Reye-like syndrome, fever, pneumonia, hypoglycemia, hyperammonemia, elevated creatine kinase, hepatomegaly, and hydrocephalus who was found to have the p.Arg471His variant and a stop-gained variant, presumably in a compound heterozygous state. In vitro studies in which the p.Arg471His variant was expressed in Chinese hamster ovary (CHO) cells displayed carnitine transport rates of <2% of wild-type (di San Filippo et al. 2006). The p.Arg471His variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Additionally, Arg471 is a conserved residue located in transmembrane domain 11, a region involved in substrate recognition and transport, and other missense variants impacting the Arg471 residue have been reported in the literature and submitted to ClinVar with likely pathogenic or pathogenic classifications for SPCD (Longo et al. 2016; Landrum et al. 2018). Based on the collective evidence and application of the ACMG criteria, the p.Arg471His variant is classified as likely pathogenic for systemic primary carnitine deficiency.
Genome-Nilou Lab	RCV000022382	SCV002055832	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022382	SCV004020911	pathogenic	Renal carnitine transport defect	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1412G>A (p.Arg471His) results in a non-conservative amino acid change located in the major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251434 control chromosomes (gnomAD). c.1412G>A has been reported in the literature as a biallelic genotype in symptomatic and asymptomatic individuals affected with Systemic Primary Carnitine Deficiency (e.g. Spiekerkoetter_2003, Han_2014, Liammongkolkul_2023). These data indicate that the variant is very likely to be associated with disease. Furthermore, publications reporting experimental evidence evaluating an impact on protein function in CHO cells found that the variant results in <2% transport activity compared to the WT protein (e.g. Amat di San Filippo_2006, Frigeni_ 2017). The following publications have been ascertained in the context of this evaluation (PMID: 16652335, 28841266, 25132046, 36321377, 14605509). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000022382	SCV004201268	pathogenic	Renal carnitine transport defect	2024-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV004700266	SCV005201425	pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing	Published functional studies involving in vitro expression of p.R471H in CHO cells demonstrate a significant decrease in carnitine transport activity compared to wild type (PMID: 28841266, 16652335); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20027113, 21922592, 25132046, 23379544, 31057083, 16652335, 28841266, 14605509)
Natera, Inc.	RCV000022382	SCV001462824	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing